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 Cancer^{a,b,48,161,182,207}

Outcomes	No. of Participants (Studies), Follow-up	Quality of the Evidence (GRADE)	Relative Effect (95% CI)	Anticipated Absolute Effects
				Risk With No Extended Duration Oral Anticoagulation	Risk Difference With Extended Duration Oral Anticoagulation (95% CI)
Mortality	1,184 (4 studies), 10-36 mo	Moderatec-e due to imprecision	RR 0.57 (0.31-1.03)	63 per 1,000	27 fewer per 1,000 (from 44 fewer to 2 more)
Recurrent VTE at 1 y	1,184 (4 studies), 10-36 mo	High	RR 0.12 (0.09-0.38)	First VTE provoked by surgeryf-j
				10 per 1,000	10 fewer per 1,000 (from 6 fewer to 9 fewer)
				First proximal DVT or PE provoked nonsurgical/first unprovoked distal DVTf-j
				50 per 1,000	44 fewer per 1,000 (from 31 fewer to 45 fewer)
				First unprovoked VTEf-j
				100 per 1,000	88 fewer per 1,000 (from 62 fewer to 91 fewer)
				Second unprovoked VTEf-j
				150 per 1,000	132 fewer per 1,000 (from 93 fewer to 137 fewer)
Major bleeding at 1 y	1,184 (4 studies), 10-36 mo	Moderate due to imprecision	RR 2.63 (1.02-6.76)	Lowk,l (see Table 2)
				3 per 1,000	5 more per 1,000 (from 0 more to 15 more)
				Moderatek,l (see Table 2)
				6 per 1,000	10 more per 1,000 (from 1 more to 29 more)
				Highk,l (see Table 2)
				25 per 1,000	40 more per 1,000 (from 3 more to 122 more)
Recurrent VTE at 5 y	1,184 (4 studies), 10-36 mo	High	RR 0.12 (0.09-0.38)	First VTE provoked by surgeryf-j
				30 per 1,000	26 fewer per 1,000 (from 19 fewer to 27 fewer)
				First proximal DVT or PE provoked nonsurgical/first unprovoked distal DVTf-j
				150 per 1,000	132 fewer per 1,000 (from 93 fewer to 137 fewer)
				First unprovoked VTEf-j
				300 per 1,000	264 fewer per 1,000 (from 186 fewer to 273 fewer)
				Second unprovoked VTEf-j
				450 per 1,000	396 fewer per 1,000 (from 279 fewer to 409 fewer)
Major bleeding at 5 y	1,184 (4 studies), 10-36 mo	Moderate due to imprecision	RR 2.63 (1.02-6.76)	Lowk,l (see Table 2)
				15 per 1,000	24 more per 1,000 (from 2 more to 73 more)
				Moderatek,l (see Table 2)
				30 per 1,000	48 more per 1,000 (from 4 more to 146 more)
				Highk,l (see Table 2)
				125 per 1,000	199 more per 1,000 (from 17 more to 609 more)
Burden of anticoagulation not reported	…	…	…	Warfarin: daily medication, dietary and activity restrictions, frequent blood testing/monitoring, increased hospital/ clinic visitsm	…
PTS not reported	…	…	…	n	…

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 and3 legends for expansion of other abbreviations.

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

^bWe 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.

^cI^{2 =} 0%.

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

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

^fAnnual 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).

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

^hAnnual 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).

ⁱAnnual 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).

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

^kAnnual 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).

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

^mBurden 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).

ⁿPTS: 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.