Luận án Study of clinical characteristic and risk factors for deep vein thrombosis of the lower extremities in patients with chronic heart failure

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF NATIONAL DEFENSE MILITARY MEDICAL UNIVERSITY HUYNH VAN AN STUDY OF CLINICAL CHARACTERISTIC AND RISK FACTORS FOR DEEP VEIN THROMBOSIS OF THE LOWER EXTREMITIES IN PATIENTS WITH CHRONIC HEART FAILURE Specialty: Cardiovascular Medicine Code: 62 72 01 41 ABSTRACT OF MEDICAL DOCTORAT THESIS HANOI - 2015 THIS RESEARCH WAS COMPLETED AT THE MILITARY MEDICAL UNIVERSITY Faculty advisor: Assoc. Prof. PhD. NGUYEN OANH OANH Reviewer 1: Prof. PhD. NGUYEN DUC CONG Thong Nhat Hospital TAssoc. Prof. PhD. PHAM NGUYEN SON Reviewer 2: Prof. PhD. NGUYEN ANH TRI National Institut of Hematology and Blood Transfusion 108 Military Central Hospita Reviewer 3: Assoc. Prof. PhD. TRAN VAN RIEP 108 Minitary Central HospitalAssoc. Prof. PhD. HA HOAN Military Medical University This thesis will be presented before the University Review Committee at: , on This Thesis can be searched at: 1. National Library 2. Military Medical University Library PROBLEM POSED Deep vein thrombosis (DVT) is always one of frequent clinical issues of hospitalized patients. Pulmonary emboli (PE) - an acute complication of DVT - can cause death. Many chronic complications of DVT such as post-thrombosis syndrome and chronic venous ulcers both damage significantly to the health of patients. Until now Vietnam, diagnosis and preventive strategies of DVT for hospitalized individuals in internal medicine or surgery departments have not been done routinely, especially in patients with chronic heart failure who usually had high risks of DVT resulted from either circulatory stasis or restriction of movements. Currently, there are not many investigations on this interesting aspect as well as on patients with chronic heart failure (HF). Clinical signs may be difficult to catch and any health centers are not equipped with essential diagnose instruments or cannot be performed intermediately. Thus, we hope this study will reveal real current evidences and how dangerous of this issue is in Vietnam. Research objectives: Describe the prevalence, clinical and para-clinical features of deep vein thrombosis at lower extremities using venous Doppler ultrasound. Identify the risk factors of deep vein thrombosis at lower extremities and its correlation to heart failure severity. 1. The subject urgency DVT is usually seen in hospitalized patients, especially in patients who have chronic diseases, are motionless or bedridden. This is an urgent problem recently because of serious impacts to public health. Furthermore, this disease is not recognized seriously in people with internal medicine problems. Not only early detection but also prophylaxis of DVT complications are important issues. In Vietnam, there are many studies but they unclearly show general approaches, and there is no thorough research about lower limbs DVT in chronic HF individuals. So, this problem has been a hard trouble to deal with, needs many essential solutions and significant realities. 2. New contributions Study has determined the prevalence of deep vein thrombosis of the lower extremities in patients with chronic heart failure NYHA class III/IV and a number of risk factors. Patients with chronic heart failure are at high risk for deep vein thrombosis and the risk increases with the functional NYHA III/ IV. The clinical symptoms of deep vein thrombosis are often atypical. Hence applying initiative and routine vascular Doppler ultrasound to diagnose is important in patients with heart failure, who normally carry higher risk of deep vein thrombosis. 3. Thesis layout There are 132 pages in this thesis. Besides parts included such as Problem posed, Conclusion, Recommendation, there are 4 chapters: Overview (38 pages), Objects and methods (19 pages), Results (30 pages), Discussions (40 pages). There are 43 tables, 14 figures, 4 charts and 143 references (20 Vietnamese, 123 English). Chapter 1 OVERVIEW 1.1. Deep vein thrombosis of the lower extremities 1.1.1. Epidemiology of deep vein thrombosis In population, the incidence of DVT in the world around 1/1000 adults each year, a more slightly higher in men than in women, increases with age and reaches 5-6/1000 per year at the age of 80. Several studies suggest that at least 2-3% of the population have DVT sometime in life. DVT is considered to be rare in Asian patients. However, several recent studies have noted an increase in the incidence of DVT in Asia. 1.1.2. Overview on deep vein thrombosis of the lower extremities Thrombus formation usually begins in the sinuses after valves due to the blood stream turbulence which leads to relatively stagnant blood flow. The formation of thrombi usually is coordinated by a variety of factors, including the three basic etiological factors, described by Virchow: the hypercoagulable blood’s state, blood vessels’ damages, and blood flow’s stasis. The risk of DVT increases in the following scenarios: - Immobility: venous blood will flow slowly. - Vein damage: increased risk DVT. - Use female hormones therapy: increases the risk of DVT. - Genetic and acquired diseases: cancer, sepsis, heart failure, pregnancy, use of oral contraceptives, obesity, over 65 year-old, making the blood clot, thus increasing the risk of DVT. 1.1.4. The workups for diagnosing deep vein thrombosis of the lower extremities 1.1.4.3. The role of venous Doppler ultrasonography in the diagnosis of deep vein thrombosis of the lower extremities In 1986, the ultrasound technique squeeze blood vessels are first described in diagnosis DVT by Raghavendra. Duplex ultrasonography uses a combination of two methods: b-mode (modulated luminance) and colorful Doppler techniques. This is the method used to detect the presence of intravascular echoic blood clots (volume occupied by blood clots) and used to evaluate the blood flow (including the shift of blood flow, direction flow, and the change in respiration). Color Doppler ultrasound allows to conduct a broad and non-invasive. Assessment color Doppler ultrasound is equal to compression ultrasound or combine multiple clinical, d-dimer testing and compression ultrasound. Color Doppler ultrasound is increasingly accepted as a means of imaging non-invasive, accurate in the case of suspected DVT. The sensitivity 95% and specificity of 98% are mentioned in many researches around the world. Intravenous compression usually causes complete collapse, while sometimes venous thrombi only against the compressive forces, or intravascular pressure is not falling. Uncollapsed veins after compressing is the sole criterion showed venous thrombosis. Color Doppler ultrasound is routinely used to identify blood vessels, especially in the deeper sections. Color fills the entire normal veins, but color flow is diminished or undetected in venous thrombosis. 1.2. Heart failure 1.2.1. Epidemiology At the age from 45 to 54, the rate of HF in males is 1.8/1,000; 4/1,000 at 55-64 and 8.2/10,000 at 65-74. On average, after ten years living, the risk rises twofold. HF is popular in patients hospitalized with HF and the most common HF among above-65-year-old people. 1.2.3. New York Heart Association Classification of Heart Failure Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnoea. Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnoea. Class III: Marked limitations of physical activity. Comfortable at rest, but less than ordinary activity results in fatigue, palpitation, or dyspnoea. Class IV: Unable to carry on any physical activity without discomfort. Symptoms at rest. If any physical activity is undertaken, discomfort is increased. 1.3.Research about deep vein thrombosis at heart failure patients 1.3.1. Risk factors of venous thrombosis embolism in heart failure Congestive HF results to an increase the venous pressure, associated with immobility of patients, will increase the risk of congestion. At HF patients, the prolonged immobility will results in slowing blood flow, decrease the ventricle blood output, congest veins, hypotension, compacted blood, secondary polycythemia which leads to venous thrombosis. The risk of venous thrombosis will increase as the EF falls down. But there are some research show that the congestive heart failure is not a risk factor of venous thrombosis embolism (VTE). 1.3.3. The incidence and the risk of venous thrombosis embolism in hospitalized heart failure patients 1.3.3.1. Worldwide Researches all over the world, especially in Europe and America, record that 10-59% congestive HF patients have DVT. Belch et al. (1981) recorded that 26% patients hospitalized with HF suffering DVT due to no thrombosis prevention. Congestive heart failure is an independent risk factor of VTE. The risk grows greatly when EF decreases. HF patients easily suffer from VTE and related complications like PE and right ventricle failure. The research of Piazza et al. shows that the HF patients is vulnerable subjects from VTE and its complications. But their research does not distinguish the systole or diastole HF, or both, and not record about the data of EF. Ota et al. (2009) had the first research in Japan about the incidence of DVT at severe congestive HF patients. The result shows that the Asian also has the risk of suffering DVT as Europe patients. 1.3.3.2. In Viet Nam INCIMEDI research (2010), the first study in Vietnam about asymptomatic DVT in hospitalized patients sufferring acute internal diseases. Dang Van Phuoc et al. recorded that the rate DVT in hospitalized patients is 21%. The rate of DVT in severe HF patients with NYHA class III/IV is 24.5%. However, there are only 20% total of HF patients. Chapter 2 SUBJECTS AND METHODS 2.1. Subjects Subjects included 136 chronic heart failure patients with New York Heart Association class III/IV, at Gia Dinh People’s hospital, in Ho Chi Minh City, from April 1, 2011 to March 31, 2013. 2.1.1. Selection criteria - Aged 18 years or older with New York Heart Association class III/IV. - Symptomatic or asymptomatic lower extremity DVT patients. - Agree to participate in study. 2.1.2. Exclusion criteria - History of DVT, PE within the previous twelve months. - Lower extremity DVT occurs in cancer patients following their therapy, pregnant women or patients suffering from surgery. - Patients who have hematologic problems. - Patients follow mechanism prophylaxis of DVT such as: compression stockings or intermittent pneumatic compression. - Not accepted to participate in study. 2.2. Methods Prospective, descriptive study. 2.2.1.5. Subgroup of study Patients will be confirmed the presence of lower extremity DVT by color Doppler ultrasound, then they will be clustered into two subgroups: DVT group and non-DVT group. 2.3. Data analysis Data will be analyzed by SPSS edition 21.0. The result of study will be presented with 95% confident interval. We use Chi-square test to compare, evaluate the difference between two rate and t-student test to compare two means. We use logistic regression model to determine related factors. P ≤ 0.05 is considered to be statistical significant. HF patients with NYHA class III/IV ECG, Chest X-ray Complete blood count PT, PT%, aPTT, INR, Fibrinogen NT-proBNP echocardiography D-dimer Non-DVT diagnostic Diagnostic DVT Risk factors, correlation between DVT and heart failure Objective 2 Clinical, echo evidences of DVT Objective 1 Lower extremity Doppler ultrasound Figure 2.1: Flow chart of study protocol Chapter 3 RESULTS 3.1. Patient characteristics Age: 73.5±12.2. NYHA III HF: 70.6%, NYHA IV HF: 29.4%. 3.2. Clinical and subclinical characteristics of lower extremity deep vein thrombosis in chronic heart failure patients Table 3.15: The percentage of DVT in heart failure patients DVT Frequency (n) Rate (%) Yes No 58 78 42.6 57.4 DVT only Combine with SVT 30 28 51.7 48.3 Table 3.18: Clinical symptoms of deep vein thrombosis Symptoms Frequency (n=58) Rate (%) Erythema 3 5.2 Pain localized to the site of thrombus 3 5.2 Swelling of the entire leg 3 5.2 Calf > 3 cm thicker than the other calf 3 5.2 Edema Two legs One leg Not edema 28 1 29 48.3 1.7 50 3.2.3. Sites and properties of deep vein thrombosis Table 3.21: Sites of deep vein thrombosis Location Frequency (n=58) Rate (%) Common femoral vein 19 32.8 Superficial femoral vein 18 31.0 Deep femoral vein 11 19.0 Popliteal vein 32 55.2 Anterior tibial vein 0 0 Posterial tibial vein 1 1.7 Peroneal vein 0 0 Table 3.23: Sites of binding and obstructive level of thrombus Thrombus Frequency (n=95) Rate (%) Sites of binding Root of valve 33 34.7 Bind to wall of vein 62 65.3 Level of obstruction Complete 8 8.4 Incomplete 87 91.6 3.3. Correlation between the clinical and subclinical characteristics of deep vein thrombosis and chronic heart failure 3.3.1. The clinical and subclinical characteristics comparison between non-DVT group and DVT group Table 3.27: The clinical and subclinical characteristics comparison between non-DVT group and DVT group Index ( ± SD) Non-DVT group (n=78) DVT group (n=58) p value Age (year) 73.0 ± 12.8 74.1 ± 11.4 > 0.5 Immobile time (day) 8.0 ± 4.1 7.6 ± 4.1 > 0.05 BMI 22.2 ± 1.3 22.9 ± 1.7 < 0.05 White blood cell (G/l) 14.42 ± 6.97 13.35 ± 6.36 > 0.05 Hematocrite (%) 34.49 ± 8.14 35.93 ± 9.19 > 0.05 Platelet (G/l) 244.42 ± 111.8 224.76 ± 97.96 > 0.05 PT (second) 14.75 ± 1.95 15.38 ± 3.89 > 0.05 PT% (%) 80.09 ± 14.81 78.51 ± 19.47 > 0.05 INR 1.20 ± 0.19 1.26 ± 0.42 > 0.05 aPTT (second) 29.02 ± 4.22 30.58 ± 10.07 > 0.05 Fibrinogen (g/l) 3.85 ± 1.22 4.47 ± 1.87 < 0.05 CRP (mg/l) 89.08 ± 80.17 92.75 ± 86.65 > 0.05 NT-ProBNP (pg/ml) 14358.61 ± 12343.90 13233.43 ± 13589.94 > 0.05 D-dimer (ng/mL) 4754.37 ± 6733.15 4897.20 ± 6206.26 > 0.05 Ejection Fraction % 51.6 ± 13.9 53.6 ± 14.9 > 0.05 3.3.4. Correlation between deep vein thrombosis and BMI, smoking Table 3.32: Correlation between deep vein thrombosis and BMI, smoking Group Non-DVT group (n=78) DVT group (n=58) OR (95% CI) p value BMI (kg/m2) (n,%) < 23 64 (82.1) 36 (62.1) 2.79 (1.26-6.12) ≥ 23 14 (17.9) 22 (37.9) p < 0.01 Smoking (n,%) No 68 (78.2) 42 (72.4) 2.59 (1.08-6.24) Yes 10 (21.8) 16 (27.6) p < 0.05 3.3.6. Relationship between deep vein thrombosis and causes of heart failure Table 3.36: Relationship between deep vein thrombosis and causes of heart failure Causes of heart failure Non-DVT group (n=78) DVT group (n=58) OR (95% CI) p value Chronic coronary artery disease (n,%) no (n=19) 6 (7.7) 13 (22.4) 0.29 (0.10-0.81) yes (n=117) 72 (92.3) 45 (77.6) p < 0.05 Rheumatic heart disease (n,%) no (n=134) 76 (97.4) 58 (100) p > 0.05* yes (n=2) 2 (2.6) 0 Hypertension (n,%) no (n=107) 62 (79.5) 45 (77.6) p > 0.05 yes (n=29) 16 (20.5) 13 (22.4) COPD (n,%) no (n=123) 74 (94.9) 49 (84.5) 3.40 (0.99-11.65) yes (n=13) 4 (5.1) 9 (15.5) p < 0.05 * Test Fisher 3.3.8. Relationship between deep vein thrombosis and ejection fraction of left ventricular (EF%) Table 3.38: Relationship between deep vein thrombosis and EF patient groups with following EF% Non-DVT group (n=78) DVT group (n=58) p value < 20% (n,%) 1 (1.3) 0 > 0.05 20-29% (n,%) 4 (5.1) 3 (5.2) 30-39% (n,%) 8 (10.3) 9 (15.5) 40-49% (n,%) 24 (30.8) 13 (22.4) ≥ 50% (n,%) 41 (52.6) 33 (56.9) < 50% (n,%) (n=62) 37 (47.4) 25 (43.1) > 0.05 ≥ 50% (n,%) (n=74) 41 (52.6) 33 (56.9) 3.3.9. Relationship between deep vein thrombosis and severity of heart failure NYHA III/IV Table 3.39: Relationship between deep vein thrombosis and severity of heart failure NYHA III/IV Severity of heart failure ( NYHA) Non DVT group (n=78) DVT group (n=58) OR (95% CI) p value NYHA III (n,%) NYHA IV (n,%) 66 (68.8) 12 (30.0) 30 (31.2) 28 (70.0) 5.13 (2.30-11.45) p = 0.0001 3.3.10. Logistic regression model Table 3.40: Logistic regression model Variables n = 136 deep vein thrombosis OR p value Ten age group 1.15 0.340 Age > 75 0.51 0.054 Immobile time 0.87 0.523 BMI ≥ 23 kg/m2 2.79 0.010 Smoking 2.59 0.034 NYHA IV 5,13 0.0001 EF% < 50% 1.19 0.616 Table 3.41: Logistic regression model Independent variables n = 136 deep vein thrombosis OR 95% CI p value Age > 75 0.63 0.28-1.44 > 0.05 BMI ≥ 23 kg/m2 1.33 0.51-3.46 > 0.05 Smoking 1.65 0.59-4.61 > 0.05 NYHA IV 4.51 1.86-10.94 0.001 Chapter 4 DISCUSSION 4.1. Patient characteristics In our study, 2/3 patients (70.6%) have HF NYHA III, and 29.4% have HF NYHA IV. The study in Japan have NYHA II, III, IV HF patients, of which only half of the patients have severe HF. 4.2 Prevalence rate and clinical, ultrasound signs of deep vein thrombosis in patients with chronic heart failure: While previous studies showed the prevalence rate of lower extremity DVT in patients with chronic HF is 11.2% in Japan and 20-40% in other countries, our prevalence is 42.6% (58/136 patients). Such a differrence is due to more severe HF in our study (we included only HF NYHA III and IV patients with the percentages of 70.6% and 29.4%, respectively). Meanwhile, the study by Ota et al. in Japan collected all types of HF, including NYHA II (42.2%), III (26.1%), IV (31.7%) patients, of which only half of the patients have severe HF. 4.2.2. Clinical symptoms of DVT of the lower extremities One important sign to identify thrombosis is swelling in one leg (edema), which is found in 70% of patients. Although leg edema is quite common among HF patients with DVT, it is not the typical sign unless it appears only in one leg. Some particular symptoms include pain and redness at the abnormal leg, the whole leg is swollen, the perimeter of the leg with DVT is larger than the normal one by about 3cm, which is only seen in 3/58 patients (5.2%). Clinical symptoms of DVT are atypical; moreover, patients with chronic HF often have leg cramps which overwhelmed DVT symptoms. Many patients with DVT have no or limited symptoms, but a high frequency of congestive HF signs, such as leg cramps, may overlap DVT signs. 4.2.3. Location and properties of deep vein thrombosis 4.2.3.1. Distribution of blood clots in deep vein thrombosis DVT occurs identically in right and left legs. We noted at the DVT rate of both legs is 32.8% (19/58 patients), often in one rather than both legs. This is similar to previous studies, both nationally and internationally. According to Ota et al., right leg thrombosis account for 44.5%, left one for 33.3%, and both for 22.2% of the total cases. On the other hand, Goldhaber et al. noted that one leg lower-extremity DVT is found in 77% of the patients, while that number is 12% for both legs. The most common DVT part is the popliteal vein (55.2%), common femoral vein (32.8%), superficial femoral vein (31%), deep femoral vein (19%). At each vein, the probability of thrombosis occurs equally in both left and right leg. We recorded 100% of patients with proximal vein thrombosis (over the knees), one patient (1.7%) had more blood clots at the distal vein (below the knee). As noted in Samama et al., the rate of DVT is 57.9% in distal vein, 23.9% in the proximal, and 16.3% in both. According to Goldhaber et al., 15.2% of the patients have DVT only in the distal vein; while 36.5% of them have both proximal and distal vein. Pham Anh Tuan et al., reported 100% of DVT in the proximal vein thrombosis (iliac and femoral vein), which is similar to our study. 4.2.3.2. Location of thrombi and complete occlusion We recorded that 65.3% of thrombi a