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Keywords:

  • monitoring;
  • quality;
  • recurrence;
  • thrombosis;
  • venous thromboembolism;
  • warfarin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Summary. Background and Aim: Several factors are associated with an increased risk of recurrent venous thromboembolism (VTE). The aim of the study was to investigate whether the quality of oral anticoagulation therapy (OAT) is a long-term risk factor for recurrence of VTE after OAT interruption. Methods and results:  A total of 297 patients (170 males) with a recent acute unprovoked VTE episode were prospectively monitored during OAT in our anticoagulation clinic and followed up for 21 months after OAT interruption. Recurrent events were recorded in 42 subjects for 493 years of follow-up [14.1% of patients; 8.5% patient-years (pt-y)] after OAT withdrawal. The rate of recurrence was not correlated to OAT duration. Subjects experiencing recurrence after OAT interruption had spent significantly more time at markedly subtherapeutic international normalized ratio (INR) levels (<1.5) and less time within the therapeutic range (2.0–3.0 INR) during OAT. Relative risk (RR) of recurrence was significantly higher [2.77 (95% confidence interval (CI) 1.49–5.18; P = 0.001) and 2.70 (95% CI 1.39–5.25; P = 0.003) at univariate and multivariate analysis, respectively] in those who spent more time (upper quintile) at INR values <1.5, being especially evident in the first 90 days of OAT. RR was significantly higher at univariate [2.05 (95% CI 1.07–3.96; P = 0.031)] but not at multivariate [1.98 (95% CI 0.98–4.0; P = 0.056)] analysis when the entire OAT period was considered. Subjects in the upper quintile of time spent at INR values <1.5 had significantly higher D-dimer values when OAT was stopped and after 3 months. Conclusions: The amount of time that subjects with an acute unprovoked VTE event spend at near-normal INR values (<1.5) during the first 3 months of treatment is associated with higher D-dimer values measured during OAT and after its interruption and is a significant risk factor for late VTE recurrence.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common and serious disorder. A first course of unfractionated or low-molecular-weight heparin (LMWH) followed by at least 3 months of oral anticoagulant therapy (OAT) is the treatment of choice in patients with acute VTE episodes. The treatment aims to prevent death after pulmonary embolism (PE), stop thrombus extension and reduce the rate of recurrence. After a first episode of VTE, the risk of recurrence is relatively high with potentially serious clinical consequences, as acute (in 5% of patients [1]) and chronic (post-thrombotic syndrome) complications are frequent. Some prospective cohort studies and randomized trials have provided estimates of recurrences after a first DVT episode. Although OAT is highly effective in reducing the risk of recurrence, new thromboembolic events may occur even during treatment (in 2.7% of patients in a large prospective cohort study [2]). Although the risk of recurrence is greatest after OAT interruption, the risk is higher in the first few months after the acute event, with an annual incidence of 5–8% [3], declining over time for a cumulative incidence of 20% after 5 years and 30% after 8–10 years [4–6].

A number of factors are associated with an increased risk of recurrence. It is well known that the incidence of recurrence is higher when the first event was unprovoked or associated with persistent risk factors such as cancer or antiphospholipid antibodies than when it was associated with transient or removable factors such as surgery, trauma, fracture and immobilization [4,5,7,8]. The persistence of a residual thrombus in the affected venous tract [9,10] or increased D-dimer levels [11–13] assessed after OAT withdrawal were the two conditions associated with a significantly higher hazard ratio for recurrence. The effect of OAT duration on the risk of VTE recurrence after the first episode has been extensively investigated in recent years [3,14–16], although the optimal OAT duration is still uncertain. To our knowledge, the effects of the quality of OAT control on the subsequent risk of recurrence have never been specifically investigated to date.

The aim of the present prospective, inception-cohort study was to examine whether the quality of OAT control, with particular reference to the amount of time spent at subtherapeutic levels, may have affected the incidence of recurrence in patients with a single previous episode of unprovoked VTE.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Design of the study and patients

All consecutive patients attending our outpatient clinic between February 1995 and December 2002 for a first acute unprovoked VTE episode (DVT of the lower limbs and/or PE) were eligible for the study. Patients were included after VTE diagnosis and prospectively monitored throughout OAT. The patients (i) who were attending our outpatient anticoagulation clinic for OAT monitoring and (ii) were being treated with warfarin or acenocoumarol (Coumadin-R, Bristol Meyer Squibb, Sermoneta, Italy; Sintrom-R, Novartis, Origgio, Italy, respectively) at the intended therapeutic intensity of 2.0–3.0 INR (target 2.5 INR) were only enrolled in the study. The choice between warfarin and acenocoumarol was left to the physician treating the patient in the initial phase. The index VTE event was considered idiopathic or unprovoked in the absence of established clinical triggering or predisposing risk factors such as surgery or trauma or prolonged immobilization or hospitalization for an acute medical illness in the previous 3 months, oral contraception or hormonal replacement therapy, pregnancy, puerperium; malignancy or antiphospholipid syndrome. Many of the DVT patients (with or without PE) were diagnosed, treated as inpatients also in other hospitals and subsequently followed up as outpatients in our clinic. Patients with recurrent VTE during OAT were not eligible for the study. Patients were also excluded from the study if they started attending our outpatient clinic more than 20 days after the beginning of treatment (including the inpatient period). The inpatient period was excluded from the analysis.

Oral anticoagulation therapy duration was suggested on the first day of attendance at our clinic for a minimum of 3 months. A clinical and instrumental evaluation was then conducted at the end of the scheduled OAT course for its possible suspension. Patients were followed up for a period of 21 months after the discontinuation of OAT so as to detect the occurrence of recurrent thrombotic events. Patients were excluded from the analysis in case of a follow-up of <300 days.

The study was approved by our institutional review committee and all the procedures were carried out in accordance with our institutional guidelines. Informed consent was obtained from all subjects.

Standard treatment of acute VTE episode

The treatment usually adopted in our institution for patients with acute VTE (excluding those with PE requiring thrombolytic treatment) includes low-molecular-weight heparin (LMWH) s.c. administration twice daily at fixed doses according to body weight, or intravenous infusion of unfractionated heparin (UFH) to reach and maintain an activated partial thromboplastin time (APTT) prolongation of 1.5–2.5 times the control value. Warfarin (first-choice drug) is usually started on the first or second day beginning with a 10 or 5 mg dose according to patient age and thereafter adjusted using a nomogram. Heparin treatment is stopped after at least 5 days and after two consecutive days with INR > 2.0 (this occurs on average after 7 ± 2 days). In patients with symptomatic PE, the treatment with heparin is often more prolonged. During their stay in our ward or at the start of their attending our outpatient clinic, all patients were informed of the scheduled treatment for their VTE episode. They are also instructed on OAT characteristics and guidelines to be followed by a personal interview with a nurse and an information leaflet. Patients with DVT are instructed to wear below-knee compression elastic stockings with 40 mmHg compression at the ankle for at least 2 years.

Monitoring of oral anticoagulation and evaluation of quality of treatment

In our clinic, OAT monitoring of patients who undergo anticoagulation treatment for a recent acute VTE episode usually includes two visits in the first week, one visit in the second week and then a visit every 2 or 3 weeks. At each visit: (a) changes in patient habits, diet, co-medication, intercurrent diseases, bleeding complications and scheduled surgical or invasive procedures are monitored by a nurse interview; (b) a prothrombin time test is performed, expressed as INR; (c) the daily anticoagulant dose for the upcoming period is prescribed and the date for next visit fixed. Data for each patient visit, including date of visit, INR value, dose prescription (mg week−1), date of next visit, logging of outcome events, are collected in a computerized system [Program for Archive, Prescription, and Monitoring of Anticoagulated Patients (PARMA) software; Instrumentation Laboratory, Milan, Italy]. PARMA is used as the database for all the collected data and results and also includes an algorithm that automatically suggests OAT dosage and the next scheduled visit, both of which require approval by the physician in charge. The use of this software has recently been shown to significantly improve the quality of treatment vs. the doctor-prescribed traditional method, even in specialized anticoagulation clinics [17].

The quality of laboratory anticoagulation control was analyzed by a specific software program that calculates the percentage of time spent at different classes of INR values [18]. Quality was assessed by calculating the percentage of time spent in the following classes of INR values: <1.5; between 1.5 and 1.99; between 2.0 and 2.9; and ≥3.0. The INR values obtained at the start of treatment during heparin therapy were excluded from analysis. INR values in each subject were analyzed for both the first 3 months and the entire period of treatment.

Follow-up after OAT interruption

The decision to stop OAT was taken during a periodic examination after a minimum of 3 months of treatment by physicians unaware of the quality of anticoagulation control during treatment. On the day of OAT discontinuation, compression ultrasonography (CUS) was performed in patients with previous DVT. The common and superficial femoral veins and the popliteal veins of both lower limbs were evaluated and the presence of venous thrombus residue (VTR) was determined according to the method of Prandoni et al. [19]. VTR was assumed to be present if the transverse diameter of the vein was >2 mm at maximal compression and absent if the transverse diameter was ≤2 mm. Physical examinations (including CUS if VTR was present at OAT discontinuation) were scheduled 3 months after OAT interruption and every 6 months thereafter.

Venous blood samples were taken on three different occasions: the day OAT was discontinued (T0), 21–37 days (T1) and 3 months (±10 days) (T3) afterwards. Plasma D-dimer levels were measured by the VIDAS D-Dimer ELISA method (bioMerieux, Lyon, France; normal <500 ng mL−1). A thrombophilia screening, performed on T1 blood samples, included: prothrombin time; APTT; fibrinogen plasma levels, antithrombin, protein C, protein S; activated protein C resistance (APCR), DNA analysis for G20210A mutation of the prothrombin gene; tests for lupus anticoagulant, factor VIII chromogenic dosage. DNA analysis for R506Q factor V mutation was performed in all cases with an APCR normalized ratio <0.80. All the tests were performed using standard methods described elsewhere [12,20]. The results of D-dimer and other blood coagulation tests were not used for management purposes.

Patients were instructed to immediately refer to our department, any symptoms attributable to a new or recurrent VTE episode. They were followed up for 21 months after OAT interruption or less in case of death, VTE recurrence, or resumption of OAT for any other indication. The patient and/or family doctor were contacted if a periodic examination was missed.

Outcome events

Objectively documented DVT recurrence and/or fatal or non-fatal PE (first event or recurrence) were considered as outcomes. Patients with DVT symptoms, in the same or contralateral leg as the previous event, were administered the D-dimer test (for its high negative predictive value) and CUS that was compared with the CUS performed in all patients at the time of OAT interruption. In cases of suspected DVT recurrence in the same leg as the index event, unequivocal non-compressibility of a previously compressible venous segment or an increase of at least 4 mm in the residual diameters were the diagnostic criteria for DVT recurrence [19]. If vein diameter changed ≤1 mm, recurrence was ruled out. In case of the vein diameter change between 1.1 and 3.9 mm, CUS was repeated 5–7 days later or contrast venography performed.

In patients presenting with symptoms compatible with PE (either first event or recurrence), diagnosis was based on the results of objective algorithms using clinical probability, ventilation–perfusion lung scanning, spiral computed tomography, CUS if indicated, and D-dimer testing [21].

All deaths were recorded and coded as attributable to a venous event or any other cause as adjudicated by two investigators (G.P. and B.C.) after collecting all the available clinical data on the case.

Statistical analysis

Differences between groups were assessed by the chi-square test (Yates’ correction) or the Mann–Whitney test as appropriate. Cumulative incidence and relative risk for recurrent VTE in patients with good or poor anticoagulation quality control was calculated by the method of Kaplan and Meier; 95% confidence intervals (CI) were calculated with an approximate method and a two-sided P-value ≤0.05 was considered to be statistically significant. The Prism statistical software package (Version 3.0; Graphpad Software Inc, San Diego, CA, USA) was used for data processing. The relative risk of VTE recurrence associated with good or poor anticoagulation quality control was analyzed with the Cox regression analysis after adjustment for age, sex, duration of OAT treatment, presence/absence of thrombophilic alterations, altered/normal D-dimer levels determined 1 month after OAT withdrawal and presence/absence of residual vein thrombosis at the moment of OAT withdrawal, using the SPSS statistical package (11.0 release).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Patients and outcomes

All the 311 consecutive patients attending our anticoagulation clinic after a first unprovoked acute DVT and/or PE episode between February 1995 and December 2002 were considered eligible for the study. Fourteen patients were excluded from evaluation because monitoring in our clinic lasted <300 days after OAT withdrawal (seven patients moved to another clinic and seven other patients moved out of town and their new addresses were not available). The present report analyzes the results obtained in 297 patients (170 males). Thrombophilia screening was performed in 281 subjects. The presence of one or more thrombophilic alterations was detected in 91 (32.4%) patients. The characteristics of the patients are illustrated in Table 1.

Table 1.  Characteristics of patients included in the study
  1. VTE, venous thromboembolism; DVT, deep venous thrombosis; PE, pulmonary embolism; OAT, oral anticoagulant therapy.

  2. *Detailed combined alterations = factor V Leiden and increased factor VIII levels (four cases), and prothrombin mutation (two cases), and protein S deficiency (one case); prothrombin mutation and increased factor VIII levels (two cases), and protein C deficiency (one case).

Number total (males)297 (170)
Age [years; median (range)] 73 (34–95)
Type of VTE [n (%)]
 Proximal DVT (no PE) (bilateral in four cases)240 (80.8)
 DVT + symptomatic PE 47 (15.8)
 Isolated PE 10 (3.4)
Subjects treated with acenocoumarol  8
Subjects examined for thrombophilic alteration(s) [n (%)]281 (94.6)
Subjects with thrombophilic alteration(s) [n (%)] 91 (32.4)
 Factor V Leiden (2 homozygous) 31
 Prothrombin mutation 23
 Protein C deficiency  4
 Protein S deficiency  2
 Combined alterations* 10
 Increased factor VIII levels (values >90th percentile) 17
 Antiphospholipid syndrome  4
Total duration of follow-up after OAT interruption (years)493
Median follow-up after OAT interruption [years, days; range (days)]  1.66, 606; 305–942

During the follow-up after OAT interruption, five patients resumed OAT for reasons other than VTE (four for atrial fibrillation, one after vascular surgery), and nine patients died of reasons other than VTE. During a total follow-up of 493 years, 42 recurrences [14.1% of patients; 8.5% patient-years (pt-y)] were recorded. The events were: 35 DVT (19 ipsilateral and 16 contralateral) and seven apparently isolated PE (with no diagnosis of associated acute DVT). In 35 cases, the recurrent events appeared to be unprovoked; in five a trigger factor was detected (chronic tuberculosis infection – one, prolonged bed rest – three, surgery for cancer – one); in two cases, the possible causes could not be investigated.

As shown in Table 2, the rate of recurrence was not different in the groups with OAT durations ranging from 3 months to >1 year. The analysis, either univariate or multivariate, of the relative risk of recurrence did not show any statistical difference according to treatment duration (data not shown).

Table 2.  Incidence of recurrent venous thromboembolism in patients according to the duration of oral anticoagulant therapy
Months of treatmentRecurrences/cases (%)Recurrences/pt-y (%)
  1. χ2 = 2.56; P = 0.464.

30/13 (0)0/26 (0)
4–622/145 (15.2)22/234 (9.4)
7–1214/90 (15.5)14/147 (9.5)
>126/49 (12.2)6/86 (7.0)

The effect of quality of anticoagulation on outcomes

The distribution of time spent at different INR classes for subjects who did or did not experience a recurrent venous thromboembolic event is shown in Table 3. The percentage of time spent at markedly subtherapeutic INR values (<1.5 INR) was significantly higher in patients with recurrence, who also spent significantly less time within the therapeutic range than the others.

Table 3.  Quality of oral anticoagulation control (percentage of time spent at different INR classes during anticoagulant treatment period for all individual subjects whether they experienced recurrent venous thromboembolic events or not [median values (range)]
 Subjects without VTE recurrenceSubjects with VTE recurrenceP-value
  1. OAT, oral anticoagulant therapy; VTE, venous thromboembolism.

<1.5 INR0 (0–40.2)1.4 (0–14)0.009
1.5–1.99 INR13.3 (0–86.9)15.3 (0–97.8)0.202
2.0–2.9 INR74.1 (3.6–100)66.2 (2.2–90.6)0.0093
≥3.0 INR7.9 (0–76.2)12.2 (0–82.6)0.277
Median OAT duration (days)176 (70–903)169 (92–435)0.584

The effect of very low INR values (<1.5) on the risk of recurrence was analyzed by calculating the percentage of time spent at INR values <1.5 for each patient (excluding the initial period of induction of anticoagulation); the calculation was performed either over the entire anticoagulation course, over the first 90 days of treatment, or else over the period following the first 90 days. Subjects whose percentage of time spent at <1.5 INR during the first 90 days of OAT was in the upper quintile had significantly higher D-dimer values measured the day OAT was interrupted and 3 months afterwards, while at T1 D-dimer increase almost reached statistical significance (Fig. 1). No effect of anticoagulation quality was observed on the venous thrombotic residue (data not shown).

image

Figure 1. D-dimer results (median and interquartile range) obtained in subjects whose percentage of time spent at <1.5 INR was distributed in the first to fourth quintiles (≤3.1%) (open bars) or in the fifth quintile (>3.1%) (black bars). The test was performed on venous blood sampled the day oral anticoagulation was discontinued (T0), 21–37 days (T1) and 3 months (±10 days) (T3) afterwards.

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The percentage of recurrent VTE and the relative risk of recurrence were then calculated in patients in the upper quintile distribution vs. all other patients. As shown in Table 4a, when the first 90 days of treatment were considered, the proportion of patients who had a recurrence (27.1% vs. 10.9%; P = 0.0036) and the relative risk of recurrence were significantly higher both at univariate and multivariate analysis in upper-quintile subjects. Figure 2 shows the cumulative incidence of recurrence in subjects in the upper quintile of percentage of time spent at INR values <1.5 vs. those in all the other quintiles; the hazard ratio was 2.77 (95% CI 1.75–8.40). When the whole treatment period was analyzed (Table 4b) the RR was higher in the upper quintile at univariate but not at multivariate analysis, while when the residual period after the first 90 days was assessed the RR was not different in the two groups (Table 4c).

Table 4.  Relative risk of venous thromboembolism recurrence according to percentage of time spent <1.5 INR
Percentage of time spent <1.5 INRNo. of subjectsNo. of recurrences (%)Univariate relative risk (95% CI)Multivariate relative risk* (95% CI)
  1. *Multivariate relative risks were calculated adjusted for age, sex, duration of OAT treatment, absence/presence of thrombophilic alterations, altered/normal D-dimer levels determined 1 month after OAT withdrawal, presence/absence of residual vein thrombosis at the moment of OAT withdrawal.

(a) During the first 90 days of oral anticoagulation treatment
 1st–4th quintiles (≤ 3.1%)23826 (10.9)1 (reference)1 (reference)
 5th quintile (>3.1%) 5916 (27.1) P = 0.00362.77 (1.49–5.18) P = 0.0012.70 (1.39–5.25) P = 0.003
(b) Throughout anticoagulation treatment
 1st–4th quintiles (≤ 3.1%)23829 (12.2)1 (reference)1 (reference)
 5th quintile (>3.1%) 5913 (22.0) P = 0.0882.05 (1.07–3.96) P = 0.0311.98 (0.98–4.0) P = 0.056
(c) During the residual period of oral anticoagulation treatment in each subject after the first 90 days of therapy
 1st–4th quintiles (≤ 0.5%)20325 (12.3)1 (reference)1 (reference)
 5th quintile (>0.5%) 5110 (19.6) P = 0.2661.68 (0.81–3.50) P = 0.1651.60 (0.72–3.56) P = 0.253
image

Figure 2. Cumulative incidence of recurrence after oral anticoagulation interruption in subjects with a previous unprovoked venous thromboembolic event who were in the upper quintile of the percentage of time spent at INR values <1.5 (continuous line) vs. those in all the other quintiles (dashed line). In each subject the first 90 days of the oral anticoagulant course were considered for analysis, after exclusion of the initial days of anticoagulation induction during treatment with unfractionated or low-molecular-weight heparin. The hazard ratio was 2.77 (95% CI 1.75–8.40).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

We prospectively evaluated a cohort of patients with a first episode of unprovoked DVT (with or without PE) who attended our anticoagulation clinic from 1995 to 2002 for OAT monitoring. These patients were followed up during OAT and for 21 months after OAT was stopped to detect recurrent events.

The results of the present study show that poor-quality OAT after a first idiopathic VTE is associated with increased long-term risk of VTE recurrence after anticoagulation is stopped. The relative risk of recurrence was in fact higher in those patients who spent a higher percentage of time at markedly subtherapeutic near-normal INR values (<1.5) during the first 90 days of treatment after the acute VTE episode. The time spent at such very low INR values was significantly higher in patients who experienced a VTE recurrence after OAT withdrawal than in those who did not.

Great attention has been paid in the literature to the influence of duration and quality of initial heparin treatment (either unfractionated or low molecular weight) on the risk of recurrence in subjects with acute VTE. An initial course of heparin treatment for 5–6 days is mandatory [22–24]. It has been suggested [25,26], albeit not by all authors [27], that inadequate initial heparin therapy predisposes to late recurrence. The mechanisms linking the quality of heparin therapy during the first few days of acute VTE treatment to late recurrence have not, to date, been explained.

It is well known that the risk of VTE recurrence during long-term treatment with oral anticoagulants is higher at subtherapeutic anticoagulation levels [28] and/or in the presence of cancer or other clinically significant medical conditions [2,29]. In recent years, the effect of oral anticoagulants on the risk of recurrence after anticoagulation suspension has been extensively investigated focusing on the duration of treatment. However, the optimal duration is still uncertain, especially for patients whose first event was unprovoked. The present study did not record any significant difference in the rate of recurrence after OAT discontinuation relating to OAT duration.

Scant attention has been paid to the possible effect of oral anticoagulation quality on the risk of recurrence after OAT interruption. Many clinical trials addressing the issue of optimal OAT duration reported detailed data on the quality of anticoagulation control. However, the relationship between subtherapeutic anticoagulation levels and the incidence of recurrence was not examined in detail. For example, Levine et al. [8] reported 60.7% of time spent in the therapeutic range (2.0–3.0 INR) and 29.6% below 2.0. Kearon et al. [14] reported 64% of the time spent in the range and 22% below 2.0. These data are quite similar to those found in our study in which the mean of time spent below INR 2.0 was 17.6% when all patients were considered. The quality of OAT has been evaluated differently in other studies. Schulman et al. [3] reported effective anticoagulant treatment (at least 75% of INR results >2.0 in each individual case) in 59–65% of patients. Pinede et al. [16] considered the treatment to be effective when the median INR was ≥2.0 and ineffective when the median INR was <2.0; no influence of these results on the outcomes of that study was found.

In the present study, detailed analysis of the quality of anticoagulation control was performed individually in a large series of patients with recent, acute, unprovoked episodes of proximal DVT and/or PE. They were examined from the start of OAT and followed up after anticoagulation was stopped. The results of this study indicate that patients who experienced VTE recurrence after OAT interruption had spent significantly less time within the therapeutic range (2.0–3.0 INR) and more time at subtherapeutic near-normal anticoagulation level (<1.5). The quality of anticoagulation during the first 3 months of treatment appears to be of crucial importance for subsequent risk of recurrence. Patients who spent more time at extremely low INR values (<1.5) during the first 90 days of treatment did, in fact, have a significantly higher rate and a higher relative risk of recurrence. The higher relative risk of recurrence was also confirmed after correction for possible confounding factors such as age, sex, presence/absence of thrombophilic alterations, altered D-dimer levels determined 1 month after OAT withdrawal (factor found to be associated with higher recurrence risk [12]), presence of residual vein thrombosis at OAT withdrawal (another documented risk factor for recurrence [9,10]). No significant differences were found when the entire anticoagulation course or the residual periods after the first 90 days were taken into account, thus corroborating the importance of the first 3 months of treatment. We did not report the effect of D-dimer and thrombotic residue in relation to late recurrences as it is the subject of a separate paper. The present study does have a number of limitations. First, the study was not designed to assess the effect of different OAT durations, so no firm conclusions in this regard can be drawn. However, the recurrence rate did not seem related to OAT duration. Secondly, only patients with an idiopathic VTE first episode were included and the results cannot be applied to patients whose thrombotic event was secondary or associated to permanent risk factors or recurrent. We chose to include only subjects with unprovoked DVT as they are usually considered separately from and at higher risk of recurrence than those with DVT which is secondary to a triggering factor. Moreover, our results may not be applicable to subjects with isolated pulmonary embolism because of their small number. In our institution, patients with isolated pulmonary embolism are more likely to be admitted to the cardiology ward and anticoagulation monitoring is also more likely to be performed by cardiologists. Thirdly, we did not compare the effect of the type of heparin – either unfractionated or LMWH – employed in the initial phase of treatment on late recurrences as, starting from 1997, LMWH was employed in the majority (about 85%) of subjects with acute DVT and the recurrence rate remained stable over the years. Fourthly, while an effect on recurrences was observed in the highest quintile spent below 1.5 INR, a dose–response was not observed and the effect was somewhat unstable probably because of the small sample size in each quintile (data not shown). Fifthly, a poor quality of anticoagulation control was associated with increased D-dimer at the time of OAT withdrawal and 3 months afterwards, but not 1 month afterwards when however it was almost significant.

Sixthly, the study was performed in only one clinical center and results may have been influenced by locally specific treatment factors. Finally, we cannot give a reasonable and thorough explanation for why subtherapeutic anticoagulation levels were not associated with a temporally related increased occurrence of clinically evident recurrent events, but were associated with an increase in the long-term risk of recurrence. We can only surmise that the time spent at very low anticoagulation levels may enhance an underlying condition of hypercoagulability. This change however may not reach the intensity – or have the time – to trigger a new thrombotic event because anticoagulation is then reverted to appropriate levels. This phenomenon, however, may help prolong a condition of hypercoagulability, the intensity and effects of which may increase over time once anticoagulation is stopped and trigger clinically evident thrombotic events. It is also worthwhile to note that subjects with recurrences spent more time above the therapeutic range than subjects without recurrences, although the difference was not statistically significant. This may indicate that subjects with recurrences might have had an unstable response to OAT or received a poor OAT management but these potential problems were not evaluated by this paper.

The clinical implications of this study are the following: (a) the first 3 months of treatment after acute VTE are of pivotal importance for the subsequent evolution of the disease; (b) during this period, the quality of OAT control should be more closely investigated with more frequent monitoring than currently performed to minimize the time spent at subtherapeutic levels; (c) finally, although not yet substantiated, LMWH supplementation can be empirically recommended when markedly subtherapeutic anticoagulation levels are detected throughout the first 3 months of treatment.

In conclusion, the present study suggests that poor-quality oral anticoagulation control, especially during the first 3 months after an acute unprovoked VTE episode, is a risk factor for increasing the rate of recurrent events after anticoagulation is stopped regardless of the duration of the previous OAT course. Further multicenter studies are warranted to confirm our observations.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
  • 1
    Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998; 279: 45862.
  • 2
    Palareti G, Legnani C, Lee A, Manotti C, Hirsh J, D'Angelo A, Pengo V, Moia M, Coccheri S. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000; 84: 80510.
  • 3
    Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332: 16615.
  • 4
    Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 17.
  • 5
    Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000; 160: 76974.
  • 6
    Heit JA, Mohr DN, Silverstein MD, Petterson TM, O'Fallon WM, Melton LJ. Predictors of recurrence after deep vein thrombosis and pulmonary embolism - A population-based cohort study. Arch Intern Med 2000; 160: 7618.
  • 7
    Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet 1992; 340: 8736.
  • 8
    Levine MN, Hirsh J, Gent M, Turpie AG, Weitz J, Ginsberg J, Geerts W, LeClerc J, Neemeh J, Powers P, Piovella F. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995; 74: 60611.
  • 9
    Piovella F, Crippa L, Barone M, Vigano D'Angelo S, Serafini S, Galli L, Beltrametti C, D'Angelo A. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with DVT recurrence and new thrombosis. Haematologica 2002; 87: 51522.
  • 10
    Prandoni P, Lensing AW, Prins MH, Bernardi E, Marchiori A, Bagatella P, Frulla M, Mosena L, Tormene D, Piccioli A, Simioni P, Girolami A. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 95560.
  • 11
    Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S. Risk of venous thromboembolism recurrence: High negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002; 87: 712.
  • 12
    Palareti G, Legnani C, Cosmi B, Valdrè L. Lunghi B, Bernardi F, Coccheri S. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation 2003; 108: 3138.
  • 13
    Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B, Weltermann A, Wagner O, Kyrle PA. D-dimer levels and risk of recurrent venous thromboembolism. JAMA 2003; 290: 10714.
  • 14
    Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 9017.
  • 15
    Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, Scannapieco G, Ageno W. Warfarin Optimal Duration Italian Trial Investigators. Three months vs. one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001; 345: 1659.
  • 16
    Pinede L, Ninet J, Duhaut P, Chabaud S, Demolombe-Rague S, Durieu I, Nony S, Sanson C, Boissel JP. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001; 103: 245360.
  • 17
    Manotti C, Moia M, Palareti G, Pengo V, Ria L, Dettori AG. Effect of computer-aided management on the quality of treatment in anticoagulated patients: a prospective, randomized, multicenter trial of APROAT (Automated PRogram for Oral Anticoagulant Treatment). Haematologica 2001; 86: 106070.
  • 18
    Rosendaal FR, Cannegieter SC, Van der Meer FJM, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 2367.
  • 19
    Prandoni P, Cogo A, Bernardi E, Villalta S, Polistena P, Simioni P, Noventa F, Benedetti L, Girolami A. A simple ultrasound approach for detection of recurrent proximal-vein thrombosis. Circulation 1993; 88: 17305.
  • 20
    Legnani C, Cosmi B, Cini M, Frascaro M, Guazzaloca G, Palareti G. High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br J Haematol 2004; 124: 50410.
  • 21
    Fedullo PF, Tapson VF. The evaluation of suspected pulmonary embolism. N Engl J Med 2003; 349: 124756.
  • 22
    Gallus A, Jackaman J, Tillet J, Mills W, Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986; ii: 12936.
  • 23
    Hull RD, Raskob GE, Rosenbloom D, Panju AA, Brill-Edwards P, Ginsberg JS, Hirsh J, Martin GJ, Green D. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322: 12604.
  • 24
    Brandjes DPM, Heijboer H, Buller HR, Derijk M, Jagt H, Ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992; 327: 14859.
  • 25
    Anand S, Ginsberg JS, Kearon C, Gent M, Hirsh J. The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous heparin. Arch Intern Med 1996; 156: 167781.
  • 26
    Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy: the emerging theme of delayed recurrence. Arch Intern Med 1997; 157: 231721.
  • 27
    Anand SS, Bates S, Ginsberg JS, Levine M, Buller H, Prins M, Haley S, Kearon C, Hirsh J, Gent M. Recurrent venous thrombosis and heparin therapy – an evaluation of the importance of early activated partial thromboplastin times. Arch Intern Med 1999; 159: 202932.
  • 28
    Palareti G, Manotti C, D'Angelo A, Pengo V, Erba N, Moia M, Ciavarella N, Devoto G, Berrettini M, Leali N, Poggi M, Legnani C, Coccheri S, Musolesi S. Thrombotic events during oral anticoagulant treatment: results of the inception-cohort, prospective, collaborative ISCOAT study. Thromb Haemost 1997; 78: 143843.
  • 29
    Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 2000; 160: 34316.