Transcript Can Rapid Risk Stratification of Unstable Angina Patients Suppress

Excess Dosing of Antiplatelet and Antithrombin
Agents in the Treatment of Non-ST-Segment
Elevation Acute Coronary Syndromes
Alexander KP et al, JAMA 2005;294:3108-16
CRUSADE is a National Quality Initiative of Duke Clinical Research, funded
Schering Corporation. Bristol-Myers Squibb/Sanofi Pharmaceuticals
Partnership provides an unrestricted grant in support of the program.
Background

Anti-platelet and anti-thrombin agents are
efficacious and thus recommended treatments for
patients with NSTE ACS (AHA/ACC Guidelines)

Current QI efforts focus on increasing their use in
this population
% Bleeding per Trial Definition
Major Bleeding in NSTE ACS Trials (and CRUSADE)
14
11.5
12
10
8
7.1
6
4.6
3
4
2.4
2
0
ESSENCE
Petersen et
al
PURSUIT
Boersma et
al
CRUSADE
Major Bleeding: ICH + HCT drop >12% or 15% drop ± transfusion
Cohen NEJM 1997; Petersen JAMA 2004; PURSUIT NEJM 1998; Boersma Lancet 2002
Purpose

Determine the frequency with which UF
heparin, LMWH, and GP IIb/IIIa inhibitors are
dosed in accordance with recommendations

Determine patient and hospital factors
associated with excess dosing

Determine the associations between excess
dosing and risk for major bleeding
Methods

All CRUSADE NSTE ACS pts (n= 30,316 at 384 sites)
 January - December 2004
 Excluded if missing dose, creatinine clearance, weight,
or transferred prior to discharge

Grouped according to acute therapy

Predictors of excess dose

Relationship btw dose and major bleeding
 Transfer and CABG patients excluded
 Major bleeding was defined as a drop in Hct ≥ 12%,
RBC transfusion, intracranial hemorrhage
Appropriate Dosing of
Acute Medications* in CRUSADE

Unfractionated Heparin
 Use weight-based dosing
 Bolus: 60- 70 U/kg  Infusion: 12-15 U/kg/hr

LMW Heparin: Enoxaparin
 Use weight-based dosing (0.95-1.05 mg/kg)

GP IIb-IIIa: Tirofiban
  Bolus to 6 µg/kg, if CrCl < 30 mL/min
  Infusion to 0.05 µg/kg/min, if CrCl < 30 mL/min

GP IIb-IIIa: Eptifibatide
  Infusion to 1.0 µg/kg, if CrCl < 50 mL/min
* Dosing information collected in CRUSADE beginning Q1 2004
Characteristics by Acute Antithrombotic Therapy
UFH
LMWH
GP IIb/IIIa
(13,298)
(12,526)
(13,967)
Age (median)
65.2
67.1
63.1
Female (%)
35.8
39.5
32.8
Renal Insuff (%)
12.5
10.7
6.8
CrCl (mean)
58.3
57.0
64.1
82
81
84
Diabetes (%)
31.8
32.8
29.3
Signs of CHF (%)
20.4
23.0
15.0
Catheterization (%)
86.7
79.0
90.7
PCI (%)
58.4
47.8
74.3
Cardiac Markers (+)
88.7
89.1
89.9
Academic Center (%)
36
22
30
Cardiologist (%)
64
56
69
Weight (median kg)
Alexander KA, JAMA 2005;294:3108-16
Predictors of Excess Dosing
UFH
LMWH
GP IIb/IIIa
Age >75
0.81
0.75
14.39
Renal Insuf.
1.25
0.82
4.12
-
0.73
3.74
1.28
1.26
1.02
Female
Weight (per 5kg ↓)
Alexander KA, JAMA 2005;294:3108-16
Excess Dose of GP IIb/IIIa Inhibitors
100
91%
90
80
70
65%
% Excess Dose
60
46%
50
40
30
26%
20
10
0
Overall
Men
Sex
Alexander KA, Circulation 2005;17:II-431
Women
<65
>75
Age (yrs)
>2.0
mg/dl
<=2.0
mg/dl
Serum Creatinine
(if CrCl <50cc/min)
Estimated Creatinine Clearance (CrCl)
Creatinine Clearance
Cockroft-Gault Calculations assuming a 150 pound woman
70
60
50
creat 1.2
creat 1.5
creat 2.0
40
30
20
10
0
60 yrs
70 yrs
Age
80 yrs
CrCl = (140-age) x weight in kg
--------------------------X 0.85 (if female)
(72 X serum creatinine)
Antithrombotic Dose and Major Bleeding
Non-CABG and Non- Transfer Population
35
Underdose
Recommended
Mild excess
Major excess
Major Bleeding (%)
30
25
20
P<0.0001
P<0.0002
P= NS
15
11.5%
10
5
0
UFH
LMWH
GP IIb/IIIa
n=6,924
n=7,484
n=8,085
Treatment Group
Alexander KA, JAMA 2005;294:3108-16
Cumulative Effects of Dosing Errors
Combined Use of Heparins and GP IIb-IIIa
25
22.2
% Major Bleeding
20
15
13.4
11.5%
10
6.6
5
0
Both Appropriate
One Excess
n=3,590 (58%)
n=2,139 (35%)
Both Excess
n=419 (7%)
Excess Dose Among Patients Given Two Antithrombotic Agents (n=6,148)
Alexander KA, JAMA 2005;294:3108-16
Adjusted Risk of Major Bleeding
(age, sex, renal insufficiency, weight, CHF, SBP)
Excess vs. No Excess

UFH
OR 1.08 (0.94 – 1.26)

LMWH
OR 1.39 (1.110 – 1.74)

GP IIb/IIIa
OR 1.36 (1.10 – 1.68)
Conclusions

Excess dosing is common for anti-thrombotic
therapies
 Disproportionately affects the thin, elderly,
women, and those with renal failure

After accounting for pt risk, excess dosing
remains a significant predictor of bleeding
 Particularly when multiple agents in excess or
major excess given
 Appropriately dosed pts have bleeding rates
approaching those in trials and better than
average community population
Optimizing Dosing of Anticoagulants
Steps for Improvement

Determine CrCl and weight for all patients upon
hospital admission
 Link drug dosing with weight and CrCl

Integrate clinical pharmacists into ED and CCU
environments to monitor dosing in “real time”

Quality metrics should monitor “how” as well as
“if” evidence-based medicines are given

Ideal comparisons between antithrombotic
strategies would consider only those patients
who receive recommended dosing