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Warfarin Better than Dabigatran and Vice Versa in Some Patients with Atrial Fibrillation

Henry I. Bussey, Pharm.D.
October, 2010

Back in March of this year ClotCare posted information on the RE-LY trial of dabigatran vs warfarin in patients with atrial fibrillation (see clotcare.org/dabigatran_vs_warfarin.aspx). One concern voiced in that posting was the degree of INR control and the lack of reporting of event rates in relation to INR control. Although I have not seen the data published, Wallentin apparently presented such a breakdown of the data at an American Heart Association meeting (see Wallentin, L. theheart.org/article/1046957.do). Comparing the data presented by Wallentin and the data contained in the original publication leads one to the following conclusions (see Table 1). The bottom quartile of warfarin-treated patients had an INR time in the therapeutic range (TTR) of < 53% which is probably similar to typical management and even consistent with some controlled trials. Compared to this bottom quartile of patients, the top 50% of warfarin-treated patients (TTR > 67%) had a greater than 50% lower composite event rate (11.9 %/yr vs 5.3%/year). Therefore, the number needed to treat for 1 year to prevent a major event (compared to the bottom warfarin quartile) is 15 patients on better warfarin control or 20 patients for either dabigatran arm. Interestingly, these differences in event rates are almost identical to those reported in a post-hoc analysis of the SPORTIF III and SPORTIF V trials (data not shown, see White HD, et al. Arch Intern Med. 2007; 167:239-245).

One might conclude, therefore, that patients whose INRs are in range > 67% of the time (RE-LY) or > 75% of the time (SPORTIF trials) may do better on warfarin than the newer agents (realizing that ximelagatran from the SPORTIF trials has been removed from the market). But for those patients with an INR TTR < 53% (RE-LY) or < 60% (SPROTIF trials), warfarin anticoagulation may be causing more harm that benefit. Table 2 presents the excess event rates that were associated with poor INR control compared to good INR control in each of these studies. In such patients, if INR control cannot be improved, perhaps warfarin should be discontinued and/or alternative therapies considered.

These event rates are based on post-hoc analyses of SPORTIF and RE-LY; but the recognized strong relationship between INR control and event rates would make it unethical to conduct a prospective trial with patients assigned to varying degrees of INR control. Furthermore, the analysis of data from a large clinic population of approximately 4,000 patients found similarly increased rates of major events in the 25% of patients with the poorest INR control (see table 3).

Table 1: Event rates by INR time in range vs dabigatran 110 BID and 150 mg BID
Event %/yr Warf n=6022 Warf Q 4
TTR < 53%
Warf Q 1-2
TTR > 67%
Dabig 110
n=6015
Dabig 150
n=6076
Stroke* + SEE 1.69 2.2 1.3 1.53 1.11**
Maj Bld 3.36 4.6 2.7 2.71** 3.11
MI 0.53 Na Na 0.72 0.74**
Total 5.58 Na Na 4.96 4.96
Death Na 7.5 2.4 Na Na
Comp. 7.64 11.9 5.3 7.09 6.91
NNT 23 --- 15.2 20.7 20.0
*"Stroke" includes hemorrhagic stroke, **stat. sig. vs warfarin in original report.
Comp = Stroke, systemic embolism, MI, PE, death, major bleeding. Warf 4th quartile = ITTR < 53.4%, 1st & 2nd quartile = ITTR > 67.1%. NNT = number needed to treat for 1 year to prevent a composite event vs warf. 4th quartile

Ref:
Connolly SJ, et al. N Engl J Med 2009; 361:1139-1151.
Gage BF. N Engl J Med 2009; 361:1200-1202.
Wallentin, L. theheart.org/article/1046957.do


Table 2 Excess Event Rates vs INR Control (per 1,000 patients per year)
  Top 1/3 vs bottom 1/3
(>75% vs < 60% TTR)
Total n=35871
Top 1/2 vs bottom 1/4
(>67% vs < 53% TTR)
Total n=6,0222
Stroke + SEE 10 9
Myocardial Infarction 8 Not reported
Maj. Bleed 22 20
Death 25 50
Total/Composite 65 66
NNT# 15.4 15.2
Comp = Stroke, systemic embolism, MI, PE, death, major bleeding.
#Number needed to treat per year to prevent one major event compared to typical INR control.
1. White HD, et al. Arch Intern Med. 2007; 167:239-245
2. Connolly SJ, et al. N Engl J Med 2009; 361:1139-1151. and Wallentin, L. theheart.org/article/1046957.do


Table 3. INR Control (%ITTR) vs Event Rates (%/yr) by Indication for Anticoagulation
End Point MI (n=1012) A Fib (n=2614) MHV (n=838)
INR ITTR % (mean)
Quartile 1-3 (mean)
Quartile 4
39
48
< 25
42
51
< 30
44
52
< 34
Thromboembolism %/YR
Quartile 1-3
Quartile 4
4
2.3
19.2
1.71
1.3
4.1
1.4
1.1
3.4
Maj. Bleed %/yr
Quartile 1-3
Quartile 4
0.9
0.8
1.9
1.6
1.3
4.1
1.7
1.4
3.9
Combined %/yr
Quartile 1-3
Quartile 4
4.9
3.1
21.1
3.3
2.6
8.2
3.1
2.5
7.3
ITTR = Individual time spent within the therapeutic INR range, MI = myocardial infarction, A Fib = atrial fibrillation, MHV = mechanical heart valve
Ref: Veeger, et al. J Thromb Haemost 2006; 4:1625-1627
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