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Error in Tables in Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Chest. 2012;142(6):1698-1704. doi:10.1378/chest.12-2089
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The article: “Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” published in the February 2012 supplement of CHEST (2012;141[2][Suppl]:e419S-e494S) contained errors in Table 18 and Table 19.

Table Graphic Jump Location
Table 18 [Section 3.1.1-3.1.4] Summary of Findings: Extended Anticoagulation vs No Extended Anticoagulation for Different Groups of Patients with VTE and Without Cancera,b,48,161,182,207

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confidence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. PREVENT = Prevention of Recurrent Venous Thromboembolism. See Table 1 and 3 legends for expansion of other abbreviations.

a 

Studies vary in follow-up duration (10 mo to 3 y) and in duration of time-limited VKA (3-6 mo).

b 

We excluded PREVENT trial because target INR was 1.75 (low intensity), which has been shown in an RCT44 to be less effective than a target of 2.5.

c 

I2 = 0%.

d 

CI includes both values suggesting no effect and values suggesting either appreciable harms or appreciable benefit.

e 

Small number of events. Decision to rate down also takes into account that two studies were stopped early for benefit.

f 

Annual risk of VTE recurrence after discontinuing oral anticoagulation therapy in patients with first VTE provoked by surgery: 1% (Iorio et al171); we assumed a 0.5% yearly risk thereafter (3% over 5 y).

g 

Annual risk in patients with first VTE provoked by nonsurgical factor: z5% the first year (Iorio et al171); we assumed a 2.5% yearly thereafter (15% over 5 y).

h 

Annual risk in patients with first episode of unprovoked VTE: 9.3% over 1 y in Rodger et al185; 11.0% over 1 y, 19.6% over 3 y, and 29.1% over 5 y in Prandoni et al.208 We assumed a risk of 10% the first year after discontinuation and 5% yearly thereafter (30% over 5 y).

i 

Annual risk in patients with second episode of unprovoked VTE: we assumed an RR of 1.5 compared with a first episode of unprovoked VTE: 15% the first year after discontinuation, 7.5% yearly thereafter (45% over 5 y).

j 

Case fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).

k 

Annual risk of major bleeding is based on three risk levels: low, intermediate, and high. The corresponding 0.3%, 0.6%, and 1.2% risks are estimates based on control arms of included studies (see Table 2).

l 

Case fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral anticoagulation therapy).

m 

Burden of anticoagulation: endured by all patients who continue extended-duration anticoagulation (100%) and applies to patients who stop anticoagulation (no extended duration anticoagulation) who subsequently experienced a recurrent VTE (5%/10%/15% at 1 y; 15%/30%/45% at 5 y).

n 

PTS: baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (Kahn et al102). There was a threefold (Prandoni et al202) to 10-fold (van Dongen et al209) increase in PTS with recurrent VTE in the ipsilateral leg.

Table Graphic Jump Location
Table 19 [Section 3.1.1-3.1.4] Estimated Absolute Difference in Recurrent VTE and Major Bleeding Events (Including Fatal Events) With 5 Years of vs No Extended Anticoagulation

Recommendations:

Risk of dying in patients with a recurrent VTE or a major bleed:

• Case fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).

• Case fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral anticoagulation therapy).

Annual risks of recurrent VTE after discontinuation of anticoagulation:

• First VTE provoked by surgery: 1% (Iorio et al171); we assumed a 0.5% yearly risk thereafter (3% over 5 y).

• First episode of VTE provoked by nonsurgical factor: z5% the first year (Iorio et al171); we assumed a 2.5% yearly thereafter (15% over 5 y)

• First episode of unprovoked VTE: 9.3% over 1 y (Rodger et al185); 11.0% over 1 y, 19.6% over 3 y, 29.1% over 5 y (Prandoni et al208). We assumed a risk of 10% the first year after discontinuation and 5% yearly thereafter (30% over 5 y).

• Second episode of unprovoked VTE: we assumed that this inflicts 1.5 the risk of recurrent VTE relative to first episode of unprovoked VTE: 15% the first year after discontinuation, 7.5% yearly thereafter (45% over 5 y).

Relative risk reduction with extended anticoagulant therapy:

• 82% based on Table 18

Annual risks of major bleeding in patients not on anticoagulant therapy:

• Low risk, 0.3%/y; intermediate risk 0.6%/y; high risk, 2.4%/y (Table 2).

Relative risk of major bleeding with extended anticoagulant therapy:

• 2.6 based on Table 18.

Criteria used to decide on direction and strengths of recommendations:

• Criterion for a strong recommendation against whenever the estimated number of fatal bleeding events exceeded the estimated number of fatal recurrent VTE prevented.

• Criterion to go from a strong recommendation against to weak recommendation against: difference between the lower boundary of increased major bleeding and upper boundary of reduction in recurrent VTE < 2% (risk over 5 y averaged per year).

• Criterion to go from a weak recommendation against to a weak recommendation in favor of: difference between point estimate of reduction of recurrent VTE and point estimate for increase in major bleeding is > 2% (risk over 5 y averaged per year) (2% to account for the burden and cost of VKA).

• Criterion to go from a weak recommendation for to strong recommendation for: difference between the lower boundary of reduction in VTE and upper boundary of increased major bleeding > 4% (risk over 5 y averaged per year).

Another way of interpreting the direction and strength of recommendation based on the number of deaths (related to either bleeding or recurrent VTE) is as follows:

• A strong recommendation against: extended anticoagulation is estimated to be associated with an increase in deaths.

• A weak recommendation against: extended anticoagulation is estimated to be associated with from no effect on deaths to only a very small reduction in deaths (0-4/1,000 prevented over 5 y or < 0.5%/patient-y).

• A weak recommendation for: extended anticoagulation is estimated to be associated with a small reduction in deaths (5 to 9/1,000 prevented over 5 y or 0.5%-0.9%/patient-y).

• A strong recommendation for: extended anticoagulation is estimated to be associated with a large reduction in deaths (. 10/1,000 prevented over 5 y or > 1%/patient-y).

a 

With an eightfold risk of bleeding in the high-risk group compared with the low-risk group, a strong recommendation against extended anticoagulation for a second unprovoked VTE is justified. The high-risk group, however, includes patients who have a risk of bleeding that is less than this estimate (eg, patients aged > 75 y without additional risk factors for bleeding [Table 2]) and, therefore, may benefit from extended anticoagulant therapy. For this reason, we provide a weak rather than a strong recommendation against extended anticoagulation for patients with a second unprovoked VTE in the high-bleeding-risk group.

b 

Strong against

c 

Weak against

d 

Weak in favor

e 

Strong in favor

There were also errors in Table S27, included in the online supplement for this chapter.

Table Graphic Jump Location
Table S27 [Sections 3.1.1-3.1.4] Extended Anticoagulation vs No Extended Anticoagulation for Different Groups of Patients With VTE and Without Cancera,b

Bibliography: Schulman et al (DURAC 2),97 Kearon et al (LAFIT),96 Farraj,98 Palareti (PROLONG).95 See Table S1, S2, S7, and S10 legends for expansion of abbreviations.

a 

Studies vary in follow-up duration (10 mo to 3 y) and in duration of time-limited VKA (3 to 6 mo).

b 

We excluded Ridker et al (PREVENT)100 because target INR was 1.75 (low intensity), which has been shown in an RCT to be less effective than a target of 2.5.

c 

I2 5 0%.

d 

CI includes both values suggesting no effect and values suggesting either appreciable harms or appreciable benefit.

e 

Small number of events. Decision to rate down also takes into account that two studies were stopped early for benefit.

f 

Annual risk of VTE recurrence after discontinuing oral anticoagulation therapy in patients with first VTE provoked by surgery: 1% (Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170(19):1710-1716); we assumed a 0.5% yearly risk thereafter (3% over 5 y).

g 

Annual risk in patients with first VTE provoked by non surgical factor: about 5% the first year (Iorio et al); we assumed 2.5% yearly thereafter (15% over 5 y).

h 

Annual risk in patients with first episode of unprovoked VTE: 9.3% over 1 y in Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179(5):417-426; 11.0% over 1 y, 19.6% over 3 y, and 29.1% over 5 y in . We assumed a risk of 10% the first year after discontinuation and 5% yearly thereafter (30% over 5 y).

i 

Annual risk in patients with second episode of unprovoked VTE: we assumed an RR of 1.5 compared with a first episode of unprovoked VTE: 15% the first year after discontinuation, 7.5% yearly thereafter (45% over 5 y).

j 

Case fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% ().

k 

Annual risk of major bleeding is based on three risk levels: low, intermediate, and high. The corresponding 0.3%, 0.6%, and 1.2% risks are estimates based on control arms of included studies (see Table 3).

l 

Case fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al) (no data available for after discontinuing oral anticoagulation therapy).

m 

Burden of anticoagulation: endured by all patients who continue extended-duration anticoagulation (100%) and applies to patients who stop anticoagulation (no extended-duration anticoagulation) who subsequently experience a recurrent VTE (5%, 10%, 15% at 1 y; 15%, 30%, 45% at 5 y).

n 

Baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (VETO [Venous Thrombosis Outcomes study]; Ann Intern Med. 2008) and threefold (Prandoni. Ann Intern Med. 2004) to 10-fold (Van Dongen. J Thromb Haemost. 2005) increase in PTS.

The online article has been corrected with the updated tables.


Figures

Tables

Table Graphic Jump Location
Table 18 [Section 3.1.1-3.1.4] Summary of Findings: Extended Anticoagulation vs No Extended Anticoagulation for Different Groups of Patients with VTE and Without Cancera,b,48,161,182,207

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confidence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. PREVENT = Prevention of Recurrent Venous Thromboembolism. See Table 1 and 3 legends for expansion of other abbreviations.

a 

Studies vary in follow-up duration (10 mo to 3 y) and in duration of time-limited VKA (3-6 mo).

b 

We excluded PREVENT trial because target INR was 1.75 (low intensity), which has been shown in an RCT44 to be less effective than a target of 2.5.

c 

I2 = 0%.

d 

CI includes both values suggesting no effect and values suggesting either appreciable harms or appreciable benefit.

e 

Small number of events. Decision to rate down also takes into account that two studies were stopped early for benefit.

f 

Annual risk of VTE recurrence after discontinuing oral anticoagulation therapy in patients with first VTE provoked by surgery: 1% (Iorio et al171); we assumed a 0.5% yearly risk thereafter (3% over 5 y).

g 

Annual risk in patients with first VTE provoked by nonsurgical factor: z5% the first year (Iorio et al171); we assumed a 2.5% yearly thereafter (15% over 5 y).

h 

Annual risk in patients with first episode of unprovoked VTE: 9.3% over 1 y in Rodger et al185; 11.0% over 1 y, 19.6% over 3 y, and 29.1% over 5 y in Prandoni et al.208 We assumed a risk of 10% the first year after discontinuation and 5% yearly thereafter (30% over 5 y).

i 

Annual risk in patients with second episode of unprovoked VTE: we assumed an RR of 1.5 compared with a first episode of unprovoked VTE: 15% the first year after discontinuation, 7.5% yearly thereafter (45% over 5 y).

j 

Case fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).

k 

Annual risk of major bleeding is based on three risk levels: low, intermediate, and high. The corresponding 0.3%, 0.6%, and 1.2% risks are estimates based on control arms of included studies (see Table 2).

l 

Case fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral anticoagulation therapy).

m 

Burden of anticoagulation: endured by all patients who continue extended-duration anticoagulation (100%) and applies to patients who stop anticoagulation (no extended duration anticoagulation) who subsequently experienced a recurrent VTE (5%/10%/15% at 1 y; 15%/30%/45% at 5 y).

n 

PTS: baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (Kahn et al102). There was a threefold (Prandoni et al202) to 10-fold (van Dongen et al209) increase in PTS with recurrent VTE in the ipsilateral leg.

Table Graphic Jump Location
Table 19 [Section 3.1.1-3.1.4] Estimated Absolute Difference in Recurrent VTE and Major Bleeding Events (Including Fatal Events) With 5 Years of vs No Extended Anticoagulation

Recommendations:

Risk of dying in patients with a recurrent VTE or a major bleed:

• Case fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).

• Case fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral anticoagulation therapy).

Annual risks of recurrent VTE after discontinuation of anticoagulation:

• First VTE provoked by surgery: 1% (Iorio et al171); we assumed a 0.5% yearly risk thereafter (3% over 5 y).

• First episode of VTE provoked by nonsurgical factor: z5% the first year (Iorio et al171); we assumed a 2.5% yearly thereafter (15% over 5 y)

• First episode of unprovoked VTE: 9.3% over 1 y (Rodger et al185); 11.0% over 1 y, 19.6% over 3 y, 29.1% over 5 y (Prandoni et al208). We assumed a risk of 10% the first year after discontinuation and 5% yearly thereafter (30% over 5 y).

• Second episode of unprovoked VTE: we assumed that this inflicts 1.5 the risk of recurrent VTE relative to first episode of unprovoked VTE: 15% the first year after discontinuation, 7.5% yearly thereafter (45% over 5 y).

Relative risk reduction with extended anticoagulant therapy:

• 82% based on Table 18

Annual risks of major bleeding in patients not on anticoagulant therapy:

• Low risk, 0.3%/y; intermediate risk 0.6%/y; high risk, 2.4%/y (Table 2).

Relative risk of major bleeding with extended anticoagulant therapy:

• 2.6 based on Table 18.

Criteria used to decide on direction and strengths of recommendations:

• Criterion for a strong recommendation against whenever the estimated number of fatal bleeding events exceeded the estimated number of fatal recurrent VTE prevented.

• Criterion to go from a strong recommendation against to weak recommendation against: difference between the lower boundary of increased major bleeding and upper boundary of reduction in recurrent VTE < 2% (risk over 5 y averaged per year).

• Criterion to go from a weak recommendation against to a weak recommendation in favor of: difference between point estimate of reduction of recurrent VTE and point estimate for increase in major bleeding is > 2% (risk over 5 y averaged per year) (2% to account for the burden and cost of VKA).

• Criterion to go from a weak recommendation for to strong recommendation for: difference between the lower boundary of reduction in VTE and upper boundary of increased major bleeding > 4% (risk over 5 y averaged per year).

Another way of interpreting the direction and strength of recommendation based on the number of deaths (related to either bleeding or recurrent VTE) is as follows:

• A strong recommendation against: extended anticoagulation is estimated to be associated with an increase in deaths.

• A weak recommendation against: extended anticoagulation is estimated to be associated with from no effect on deaths to only a very small reduction in deaths (0-4/1,000 prevented over 5 y or < 0.5%/patient-y).

• A weak recommendation for: extended anticoagulation is estimated to be associated with a small reduction in deaths (5 to 9/1,000 prevented over 5 y or 0.5%-0.9%/patient-y).

• A strong recommendation for: extended anticoagulation is estimated to be associated with a large reduction in deaths (. 10/1,000 prevented over 5 y or > 1%/patient-y).

a 

With an eightfold risk of bleeding in the high-risk group compared with the low-risk group, a strong recommendation against extended anticoagulation for a second unprovoked VTE is justified. The high-risk group, however, includes patients who have a risk of bleeding that is less than this estimate (eg, patients aged > 75 y without additional risk factors for bleeding [Table 2]) and, therefore, may benefit from extended anticoagulant therapy. For this reason, we provide a weak rather than a strong recommendation against extended anticoagulation for patients with a second unprovoked VTE in the high-bleeding-risk group.

b 

Strong against

c 

Weak against

d 

Weak in favor

e 

Strong in favor

Table Graphic Jump Location
Table S27 [Sections 3.1.1-3.1.4] Extended Anticoagulation vs No Extended Anticoagulation for Different Groups of Patients With VTE and Without Cancera,b

Bibliography: Schulman et al (DURAC 2),97 Kearon et al (LAFIT),96 Farraj,98 Palareti (PROLONG).95 See Table S1, S2, S7, and S10 legends for expansion of abbreviations.

a 

Studies vary in follow-up duration (10 mo to 3 y) and in duration of time-limited VKA (3 to 6 mo).

b 

We excluded Ridker et al (PREVENT)100 because target INR was 1.75 (low intensity), which has been shown in an RCT to be less effective than a target of 2.5.

c 

I2 5 0%.

d 

CI includes both values suggesting no effect and values suggesting either appreciable harms or appreciable benefit.

e 

Small number of events. Decision to rate down also takes into account that two studies were stopped early for benefit.

f 

Annual risk of VTE recurrence after discontinuing oral anticoagulation therapy in patients with first VTE provoked by surgery: 1% (Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170(19):1710-1716); we assumed a 0.5% yearly risk thereafter (3% over 5 y).

g 

Annual risk in patients with first VTE provoked by non surgical factor: about 5% the first year (Iorio et al); we assumed 2.5% yearly thereafter (15% over 5 y).

h 

Annual risk in patients with first episode of unprovoked VTE: 9.3% over 1 y in Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179(5):417-426; 11.0% over 1 y, 19.6% over 3 y, and 29.1% over 5 y in . We assumed a risk of 10% the first year after discontinuation and 5% yearly thereafter (30% over 5 y).

i 

Annual risk in patients with second episode of unprovoked VTE: we assumed an RR of 1.5 compared with a first episode of unprovoked VTE: 15% the first year after discontinuation, 7.5% yearly thereafter (45% over 5 y).

j 

Case fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% ().

k 

Annual risk of major bleeding is based on three risk levels: low, intermediate, and high. The corresponding 0.3%, 0.6%, and 1.2% risks are estimates based on control arms of included studies (see Table 3).

l 

Case fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al) (no data available for after discontinuing oral anticoagulation therapy).

m 

Burden of anticoagulation: endured by all patients who continue extended-duration anticoagulation (100%) and applies to patients who stop anticoagulation (no extended-duration anticoagulation) who subsequently experience a recurrent VTE (5%, 10%, 15% at 1 y; 15%, 30%, 45% at 5 y).

n 

Baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (VETO [Venous Thrombosis Outcomes study]; Ann Intern Med. 2008) and threefold (Prandoni. Ann Intern Med. 2004) to 10-fold (Van Dongen. J Thromb Haemost. 2005) increase in PTS.

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