CURAVTIVE Domain 4: monitoring

Question 1

majority of the literature pertaining to therapeutic monitoring of antithrombotic drugs was either performed in experimental animal models of disease or involved studies of drug pharmacokinetics and pharmacodynamics in healthy laboratory animals.

The final guidelines recommend:
therapeutic monitoring should be performed when using:

insufficient evidence to make strong recommendations for therapeutic monitoring of:

Answer 1

warfarin
unfractionated heparin
in dogs and cats at risk of thrombosis

aspirin or low molecular weight heparin in dogs and cats at this time.

Question 2

4.1 Aspirin

monitor how:

Answer 2

Adjusting therapy to achieve platelet inhibition via platelet aggregometry in dogs receiving aspirin therapy can be considered.

Some evidence suggests that in dogs receiving aspirin, platelet inhibition detectable via aggregometry is associated with reduced risk of ATE

Monitoring techniques are currently too varied to provide uniform recommendations at this time.

Delphi process: 14/14 panel members responding agreed (round 1).

Several LOE 3 studies suggest that platelet inhibition detectable by aggregometry is associated with reduced risk of ATE; however, there is considerable variation in the agonists used for aggregometry in different studies

overall, they suggest aspirin has limited antiplatelet efficacy in cats, particularly against potent platelet agonists

Question 3

4.2 Warfarin

Answer 3

we suggest warfarin should not be used in dogs or in cats

If warfarin is used, we recommend monitoring warfarin therapy ideally with PTINR (PT—prothrombin time; INR—international normalized ratio) to achieve a target of 2–3 or 1.5–2.0 times the baseline

One panel member felt that the guideline should indicate that continuous (ideally weekly) monitoring is advisable given the reported variability in warfarin pharmacokinetic and the potential for interactions with concomitant medications.

Of the 20 dogs reported across the 2 studies, 9 dogs died of confirmed or suspected thrombosis despite INR monitoring of warfarin therapy

Question 4

4.3 Unfractionated heparin

We recommend:
because:

target of:

Answer 4

4.3 Unfractionated heparin

anti‐Xa activity for UFH monitoring
in dogs because evidence supporting the use of other monitoring tests (eg, activated clotting time, APT activated partial thromboplastin time, TEG, and Sonoclot) is limited at this time

0.35–0.7U/mL is recommended in dogs to minimize thrombosis risk and improve outcome, although minor hemorrhage may still occur

Question 5

There is insufficient evidence to make a strong recommendation for a specific anti‐Xa target in cats.

The Helmond et al study and a second prospective study (LOE 2, Fair) indicate that:

Answer 5

We suggest an anti‐Xa target of 0.35–0.7U/mL is reasonable in cats until more evidence is available.

Delphi process: 13/13 panel members responding agreed (round 2)

anti‐Xa activity is the criterion (gold) standard for UFH monitoring

Additional studies (LOE 3, Fair–Poor) suggest that other hemostatic tests may have a role in monitoring UFH in dogs but clinical utility remains to be demonstrated

No studies in cats directly addressed the PICO question. One study suggests that the anti‐Xa assay is the standard method for UFH monitoring in cats and that achievement of anti‐Xa activity of 0.3–0.7 U/L causes anticoagulation in cats.

Question 6

4.4 Low molecular weight heparin

Four experimental studies in dogs (LOE 3, Good–Fair) addressed the PICO question, but provide limited evidence relevant to clinical practice. Various monitoring tests for LMWH in dogs including:

The anti‐Xa assay appears to be the most sensitive test of the anticoagulant effect of LMWHs in dogs

No studies in cats specifically addressed either of the relevant PICO questions and there is considerable variation in:

Answer 6

insufficient evidence to make strong recommendations for therapeutic monitoring of LMWH in dogs or cats

We suggest adjusting therapy in dogs, targeting anti‐Xa levels of 0.5–1.0U/mL 2–4 hours after dose can be considered

Delphi process: 12/12 panel members responding agreed (round 3).

anti‐Xa activity, activated partial thromboplastin time, thrombin time, activated clotting time, thromboelastography, and the Sonoclot assay have been evaluated

Two studies (LOE 3, Fair–Poor) demonstrated a protective effect of achieving an anti‐Xa activity of 0.55–0.9 U/mL in dogs using LMWH
demonstrated safety at this dose

anti‐Xa activity achieved in cats after SC administration of LMWH; however, peak anti‐Xa activity appears to occur at around 2 hours after SC dosing in this species