European Journal of Cardiovascular Medicine

Each year millions of patients experience venous thromboembolic events. Deep Vein Thrombosis (DVT) is an unfortunate and potentially preventable condition which can have life threatening sequelae in the form of fatal pulmonary thromboembolism (PTE). The annual incidence of venous thromboembolism is approximately 0.1%; the rate increases from 0.01% among persons in early adulthood to nearly 1% among those who are 60 years old. [1] The incidence also increases with age, with a 200-fold increase between ages 20 and 80 years. [2, 3] Hospitalization for an acute medical illness is independently associated with about an eight-fold increased relative risk for VTE. DVT occurs when natural anticoagulation and fibrinolytic systems are overcome by a procoagulant setting. [5]

Although VTE in the surgical setting has been well-studied, its prevalence among hospitalized medical patients has not been established in large clinical trials in our country. However, studies from the west; MEDENOX study of 1,102 hospitalized medical patients, approximately 15% of patients had VTE [6] and in other studies from the West the incidence of VTE has been reported to range from 13 to 31% among medical patients. [8, 9, 10, 11] Although the lack of symptoms and low autopsy rates (approximately 45%) make it difficult to determine the exact incidence of fatal PE among general medical patients. Mortality that is attributable to PE is thought to be particularly high among hospitalized patients with acute medical illness and 7.6% of autopsied deaths in nonsurgical hospital patients were caused by PE. [12]

Thromboprophylaxis for VTE in hospitalized medical patients is based on its high prevalence, clinically silent nature, and associated morbidity and mortality. The implementation of thromboprophylaxis in the medically ill can be challenging because these patients tend to be older, suffer from multiple comorbidities, and receive medications that may interact with prophylactic therapies for VTE.

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are currently being used for the prevention of VTE in hospitalized patients with the acute medical illness.

Various studies in the West have shown that thromboprophylaxis with low molecular weight heparin (LMWH) for a period of 06– 14 days, significantly reduces by 63% the risk of VTE in patients with the acute medical illness. [6]

In our study, thromboprophylaxis was given with LMWH (Enoxaparin / Dalteparin) for 07 to 14 days or more depending upon the clinical condition of the patient after thoroughly evaluating risk and benefits in these acutely ill medical patients admitted to a tertiary care hospital.

OBJECTIVES

• To determine the frequency of VTE in acutely ill medical patients admitted to a tertiary care
• The role of VTE prophylaxis in the outcome of the acutely ill medical patient, admitted to the same
• To evaluate the safety profile of LMWH (Enoxaparin or Dalteparin) administered for a period of 07-14 days or more if clinically indicated.

This study was conducted at the tertiary care hospital during the period 1^st Jun 2021 to 30^th Jun 2022. The study included 314 consecutive patients. These patients were admitted for acute medical illness and those who satisfied the inclusion criteria were given thromboprophylaxis for 7-14 days or more if clinically indicated either with LMWH (Enoxaparin 40/60mg OD subcutaneously S/C or with Dalteparin 5,000 Units S/C OD). Regular follow up of patients was done to assess the frequency of DVT in these acutely ill medical patients and to evaluate the safety profile of LMWH used in this subset of patients.

Inclusion criteria

Patients who are 30 years or older admitted to the hospital with acute medical illnesses.

Exclusion criteria

• Pregnancy
• Patient on /requiring dialysis
• Intracranial hemorrhage
• Major surgery within the past three
• Contraindications for anticoagulation:
• Patient has received any antiplatelet drug or oral anticoagulant treatment for more than 48 hours
• Generalized hemorrhagic diathesis or platelet count <100,000/cu mm
• Heparin-Induced Thrombocytopenia (HIT)
• International Normalized Ratio (INR) > 2

Fig. 1: Algorithm for diagnosing DVT

Informed consent was taken. All the patients were subjected to a detailed physical and clinical examination.

The patients were given LMWH (Enoxaparin 40/60mg SC OD or Dalteparin 5,000 Units S/C OD) by a qualified nurse, after carefully selecting the patient once daily for a period of 07-14 days and the duration was extended if clinically indicated. Enoxaparin was used in 30% of cases and Dalteparin in 70% of cases based on the availability of the drugs in the hospital. Patients were followed up weekly for 4 weeks and each time the clinical examination was done to rule out VTE.

Baseline D-dimer test was done on day 01 and repeated after 7 days.

Color Doppler Flow Imaging (CDFI) of the deep veins of lower limbs was done in all patients on day 1 and day 7-10.

The patients were assessed for hemorrhagic episodes during hospitalization and outpatient visits, while on LMWH prophylaxis. Bleeding severe enough to require significant medical intervention, such as transfusion or surgery, resulting in serious morbidity or mortality, was classified as major. The bleeding was classified  as minor if it was over, that did not meet the criteria for major bleed and was associated with at least one of the following features: epistaxis lasting more than five minutes or requiring intervention, ecchymosis or hematoma larger than 5 cm at its greatest dimension, hematuria not associated with urinary catheter-related trauma, gastrointestinal hemorrhage not related to intubation or placement of a nasogastric tube, or subconjunctival hemorrhage necessitating cessation of medication. [7]

Patient characteristics

1. Number of patients: In the prospective arm of the study, patients hospitalized for acute medical illness were included from 1 Jun 2021 to 30 Jun 2022. A total of 314 patients were given thromboprophylaxis.
2. Age: Age group of patients at the time of presentation varied from 31 to 72 years with mean age of 35 yrs.
3. Weight: The weight of the patients varied from 35 to 78 kg with a mean weight of 57.75 kg.

3. Sex: Out of 314 cases, 171 cases (54.46 %) were males and 143 cases (45.54%) were

4.  Diagnosis of patients who were given thromboprophylaxis is as per table 1.

Table 1: Diagnosis in patients who were given thromboprophylaxis

5. Co-morbidities: Out of 314 patients who underwent thromboprophylaxis for acutely ill medical illness, the main comorbidities were Hypertension alone in 74 cases (41.5%), Diabetes mellitus in 33 cases (18.5%), Hypertension and Diabetes mellitus in 27 cases (15.2%), Hypertension and Coronary artery disease in 16 (8.98%), Hypertension, Coronary artery disease and Diabetes mellitus in 12 cases (6.76%), Atrial fibrillation in 09 cases (5.1%). One patient who died of DVT and PTE had diabetes mellitus, hypertension, and CAD. This patient was not on thromboprophylaxis with LMWH.

3.         Investigation profile:

• Coagulation parameters: Coagulation parameters, including PT, PTTK, and Fibrinogen were deranged in 04 cases of thromboprophylaxis group, in the patients with acute Infection (03) and disseminated tuberculosis (01). Transient thrombocytopenia occurred in six patients (< 2%), suffering from acute Infection (5 patients) and Disseminated tuberculosis (01)
• D-dimmer: The baseline D-dimer values were normal (<0.5 µg/ml). Repeat D-dimer values were raised (>0.5 µg/ml) in 4 cases (03 cases of septicemia and 01 cases of Paralytic stroke).

• CDFI: CDFI deep veins of both legs were reported as normal on day 1/ on admission and Proximal DVT were found in 04 patients at the 7-10^th day in the thromboprophylaxis group were put on oral anticoagulation for three months, INR was maintained between 2.5-3 and they were followed up for a period of 3 months, uneventfully.

(d)  Abnormal laboratory tests:

Table 2: Abnormal laboratory tests

Abnormal laboratory tests in the form of deranged LFT were seen in the patient of acute Infection (11 cases), Disseminated tuberculosis (05 cases) and in 02 cases of Pyogenic meningitis. Three cases of Acute Infection who developed DVT also had deranged LFT. However, one case with DVT and Paralytic Stroke had normal LFT.

Serum creatinine was deranged in 03 cases of Diabetic nephropathy 04 cases of SLE with lupus nephritis. Blood sugar levels were maintained below 180 mg/dl by insulin infusion.

4.  Safety results:

• Hemorrhage:

 Major hemorrhage: Of the 314 patients, 9 (< 3%) had a major bleeding episode, manifested as upper gastrointestinal bleeding (08 cases) and hematuria in (01 cases) requiring stopping of thromboprophylaxis in the thromboprophylaxis group.

 Minor a hemorrhage: 38 patients (12.1%) had minor bleeds, in the form of local hematoma over the injection site (35 cases) and minor epistaxis in (03 cases), however, thromboprophylaxis was continued.

(b)  Local irritation:

Local irritation in the form of pruritus was seen in 29 (9.24%) patients who used LMWH which responded to symptomatic treatment and LMWH was not discontinued in any of the patients during the period of study.

Fig. 2: Graph showing safety profile of LMWH

5. Outcome: Of the 314 patients (treatment group) who underwent thromboprophylaxis for various medical

(a)  The frequency of (VTE):

 Proximal DVT: 4 cases (1.27 %)

 PTE: Nil

(b)  There were 07 deaths (2.2%)

 Acute Infection (Septicemia) - 4

 Refractory CHF-2

 Acute myocardial infarction – 1

Fig. 3: Graph showing outcome of Thromboprophylaxis

6. Retrospective Data: (thromboprophylaxis not given)

Table 3: Retrospective Data

7. Comparison of perspective with Retrospective Data:

Table 4: Comparison of perspective with Retrospective Data

P value by Fisher exact test = 0.018

Thromboprophylaxis with LMWH (Enoxaparin/Dalteparin) for acutely ill medical illnesses was safe and effective. MEDENOX, PREVENT, and ARTEMIS studies have brought out the importance of thromboprophylaxis, in acutely ill medical patients. [6,13,14] MEDENOX study had 1102 patients randomized with LMWH; Enoxaparin (40 mg and 20 mg and placebo). The incidence of VTE in thromboprophylaxis group was 5% and the placebo group was 14.9%.

PREVENT trial had 3681 patients, randomized with LMWH, Dalteparin (5,000 U) with placebo. The incidence of VTE in thromboprophylaxis group was 2.77% and in placebo group 4.96%.

ARTEMIS study had 849 patients; randomized with a low dose of an anti-Xa agent; (Fondaparinux 2.5 mg with placebo). The incidence of VTE in thromboprophylaxis group was 5.6% and in placebo group was10.5%. Thromboprophylaxis was given for a maximum of 14 days in all groups^.

In our study, the control group comprised of 6416 patients where medical documents were perused from January 2004 to Dec 2006 for the prevalence of VTE in acutely ill medical patients. Out of 6416 patients, the prevalence of VTE was 3.5%. The thromboprophylaxis group was based on the inclusion and exclusion criteria already elaborated in the materials and methods. We evaluated the frequency, efficacy, and safety of thromboprophylaxis (7-14 days) by using LMWH (Enoxaparin or Dalteparin) in acutely ill medical patients. Thromboprophylaxis was started within 24 hours of hospital admission. The presence of DVT had to be excluded on admission for the inclusion of the patients in the study which was done by CDFI, D-dimer and clinical examination. Out of 314 patients who underwent thromboprophylaxis, the mean age of the patients was 58.4 yrs (31 to 72 years); 171 cases (54.45 %) were males and 143 cases (45.54 %) were females.

CDFI of both lower limbs were reported normal on day 1 and distal DVT was found in these 04 patients on day 7-10 in the thromboprophylaxis group. They were put on oral anticoagulation and INR was maintained between 2.5-3.0. They were followed up for a period of 3 months uneventfully.

Thromboprophylaxis was well tolerated and safe. 09 patients (<3% of patients) had major bleeds and in 38 cases (12.1% of patients) there was minor bleed. Local irritation was noted in 29 cases (9.24 % of patients) while transient thrombocytopenia was noted in 6 cases (<2 % of patients in the acute infection group). There were 07 deaths (2.2%); Acute Infection (04), Refractory Congestive heart failure (02), Acute MI (01) comprised the cause of deaths. These figures are comparable with the existing literature.

In our study, the frequency of VTE in patients of acute medical illness was 1.27 % in the prospective arm (thromboprophylaxis group) and sub-group analysis revealed higher frequency VTE in patients suffering from Acute Infection (Sepsis) as compared to various other co-morbid medical conditions. The frequency of VTE in patients of acute medical illness in the retrospective group of patients in whom thromboprophylaxis was not given was 3.5 % (p-value = 0.018), showing a significant reduction in the frequency of DVT occurrence in acutely ill medical patients when administered thromboprophylaxis with LMWH (Enoxaparin/Dalteparin). However, one drawback in the retrospective group of patients is that no screening for asymptomatic DVT was done; hence the actual incidence could have been higher than noted and also the incidence of any major bleed could not be determined in that group.

Nevertheless, these figures are much lower than that of the Western figures as already enumerated. [8, 9, 10, 11]

Most critically ill medical patients have multiple risk factors for VTE. Some of the risk factors predate admission and include advanced age, immobilization, sepsis, stroke, heart and respiratory failure. Other thrombotic risk factors may be acquired during a stay in a hospital, which includes immobilization, central venous access, use of pharmacologic paralysis, sedation, and sepsis. The mean duration of thromboprophylaxis was 10 days (range 07-14 days).

In conclusion, thromboprophylaxis with either LMWH or Dalteparin significantly reduced the frequency of VTE in patients suffering from acute medical illness without any significant major bleed.

• The frequency of DVT in 314 consecutive acutely ill medical patients, admitted to a tertiary care hospital who underwent thromboprophylaxis with LMWH (Enoxaparin), was found to be 1.27%. However, sub-group analysis revealed higher frequency VTE in patients suffering from Acute Infection (Sepsis) as compared to various other co-morbid medical
• The thromboprophylaxis (7 -14 days) with subcutaneous LMWH/Dalteparin was found to be
• LMWH/Dalteparin was found to be safe with no significant side
• The mean duration of thromboprophylaxis was 10 days (range 07-14 days), who underwent thromboprophylaxis for various medical illnesses with LMWH (Enoxaparin).
• Therefore, it is strongly recommended that thromboprophylaxis to be administered in all acutely ill medical patients, who are at risk of developing VTE provided there is no contraindication to use of LMWH/Dalteparin.

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