Evaluation of 2 Weight-Based Protocols: RESULTS part 2

21 Dec
2010

venous thromboembolism

In both of the 2006 protocol groups, there was no statistical difference in the median time to achieve PTT above the lower limit of the target range between patients who received a full bolus dose and those who did not receive a full bolus (standard protocol 6.0 h [4.0-24.0 h] versus 6.0 h [4.0-40.8 h], p = 0.41; lower-target protocol 6.0 h [4.5-14.3 h] versus 6.9 h [4.8-39.5 h], p = 0.12). Similar results were observed for the median time to achieve PTT within the therapeutic range (standard protocol 13.8 h [4.0-36.3 h] versus 21.5 h [5.5-55.0 h], p = 0.20; lower-target protocol 14.4 h [4.5-24.5 h] versus 14.1 h [4.8-36.8 h], p = 0.39). Notably, the administration of a full bolus dose of heparin did not affect initial supratherapeutic PTTs (standard protocol 122 s [55-200 s] with bolus dose versus 132 s [46-200 s] with no bolus dose, p = 0.72; lower- target protocol 103 s [43-200 s] with bolus dose versus 80 s [52-200 s] with no bolus dose, p = 0.17).

Complete compliance with the protocols appeared higher in the current study than in the 1996 study1; nonetheless, protocol violations were documented for 29% of all patients in the current study (Table 3). Twenty errors were identified for 16 patients in the standard protocol group and 18 errors for 13 patients in the lower-target group; 49 errors were documented for 32 patients in the 1996 study. The majority of errors were due to incorrect adjustments of the infusion rate and incorrect sampling times for initial PTT measurements. In general, patients with no protocol violations achieved the primary outcomes more quickly. In the standard protocol group, although there was no difference in time to achieve PTT above the lower limit, the time to achieve PTT within the therapeutic range was significantly shorter for patients with no protocol violations. In the lower-target protocol group, time to attain PTT above the lower limit was significantly shorter for patients with complete protocol compliance. However, for this group there was no statistical difference in time to achieve PTT within the target range whether or not there were protocol violations.
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Table 3. Protocol Violations

Violations and Effects

2006
Standard

2006
Lower
Target

1996
Study1

Protocol (n = 50)

Protocol (n = 50)

(n= 50)


No protocol violations (no. and

%
of patients)


34 (68)


37 (74)


18 (36)

Protocol violations (no. and

%
of violations)


Total number of violations


20 18


49


Incorrect adjustment of infusion rate


7 (35)


5 (28)


18 (37)


Incorrect sampling time for initial
PTT


3 (15)


7 (39)


24 (49)*


Incorrect bolus dose


3 (15)


0


3 (6)


Incorrect infusion hold time


3 (15)


1 (6)


NA


Omission of documentation of PTT


2 (10)


0


NA


Omission of PTT test(s)


1 (5)


4 (22)


4 (8)


Physician not notified


1 (5)


1 (6)


0


Effect
on primary outcomes (median and range)


Time to
PTT

>

lower limit
of therapeutic range (h)


For patients with no protocol
violation


6.0 (4.0-26.5)t


6.3 (4.8-14.3)Ф


NA


For
patients with at least


1

protocol
violation



6.0
(4.0-40.8)t


11.1 (5.5-53.0)Ф


NA



Time to PTT within therapeutic range
(h)


For patients with no protocol
violation


12.8 (4.0-55.0)§


14.0 (4.5-36.8)1


NA


For patients with at least 1 protocol violation


22.0 (5.5-40.8)§


20.3 (6.0-53.0)1


NA

Adverse events were infrequent in the current study (Table 4). Only one major bleeding episode occurred in a patient in the lower-target protocol group. In the 1996 study, there were 5 episodes of major bleeding. A total of 3 deaths occurred in the current study, 2 in the standard protocol group and 1 in the lower-target protocol group. One of the deaths in the standard protocol group may have been due to treatment failure for pulmonary embolism, since the PTT was subtherapeutic for more than 30 h before the time of death. However, this patient had other serious comorbidities, including heart failure and pneumonia, which may have been contributing factors. The PTT in this patient was initially therapeutic, at 14 h after heparin initiation, but fell to 64 s by 22 h and remained subtherapeutic. Following the PTT measurement at 22 h, 2 protocol violations occurred: the heparin infusion rate was not increased and a sample for repeat PTT was not drawn for another 30 h, at which point the PTT remained subtherapeutic (60 s). At that point, the infusion rate was increased appropri­ately to reflect the measured PTT, but the patient died 6 h later. The second death in the standard protocol group involved a patient who died secondary to cardiac arrest. The third death (in the lower-target protocol group) occurred in a patient who fell 1 week after initiation of heparin for acute coronary syndrome. Heparin was continued for 2 days after the fall until an extensive right intralobar hemorrhagic stroke was discovered. The PTT at the time of this diagnosis was therapeutic (70 s) and heparin was neutralized with protamine. The patient died shortly thereafter. No arterial thromboembolic events were noted in this study. The 1996 study reported 2 cases of recurrent deep vein thrombosis or pulmonary embolism, and 3 deaths in total. One of these deaths was due to recurrent deep vein thrombosis and/or pulmonary embolism, whereas the other 2 were not attributed to heparin therapy.
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Table 4. Adverse Events

Protocol; No. (%) of
Patients*


Event


2006
Standard


2006
Lower-Target


1996
Study
1

Protocol
(n


= 50)

Protocol
(n


= 50)

(n

= 50)


Major bleeding episode


0


1 (2)


5 (10)


Recurrence of DVT or PE


0


0


2/43 (5)


Arterial thromboembolic disease


0


0


0


Death


Due to major bleeding


0


1 (2)


0


Due to DVT or PE


1 (2)*


0


1 (2)


Other cause


1 (2)


0


2 (4)

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