a vitamin K antagonist that has a narrow therapeutic index and its actions are affected by a variety of actors.

Must be monitored

• measures the time needed for blood to clot in the presence of thromboplastin and calcium. Most commonly used for warfarin. Values form the PT are calibrated with the international reference preparations to produce an international Normalized ratio (INR) which is used to standardize reporting. INR needs to be determined daily after initial dosing until values stabilize in therapeutic range and after that every 1-4 weeks. Warfarin therapy is dosed to maintain INR from 2 to 3 with a target of 2.5

• C = CHF: 1 point
• H = history of hypertension: 1 point
• A = 75 years or older: 1 point
• D = diabetes: 1 point
• S = history of stroke or TIA: 2 points

Low = 0 = ASA 81-325 mg.

Moderate = 1 = ASA or Warf.

High = 2 or more = Warf.

UPDATE includes statement that Dabigatran is useful as an alternative to Warfarin and Clopidogrel plus asa may reduce the risk of vascular events.

update to chads has the following:

C: = CHF

H: = Hypertension

A: = Age 65-74 (1pt) >75 2pts.

D: = Diabetes

S: = Stroke

V: = Vascular Disease

Sc: = Sex Category = Female 1 pt.

Sex: = Female = 1point

D

• HAS-Bled Scale

a scale to determine risk of major bleeding:

1. Hypertension = 1
2. Abnormal renal and or liver function = 1 point each
3. stroke = 1
4. bleeding = 1
5. labile inrs = 1
6. elderly (≥65 years) = 1
7. drugs and /or alcohol = 1

a score ≥ 3 indicates high risk for major bleeding

1. AFASAK (copenhagen AF asa and anticoagulation trial)
2. SPAF I (stroke prevention in AF)
3. BAATAF (Boston area anti coagulation trial in AF
4. CAFA (Canadian AF Anticoagulation)
5. SPINAF Stroke Prevention in Nonrheumatic AF)
6. EAFT (SECONDARY) European AF

38%

absolute risk reduction was 0.7% for primary prevention and 7.0% for 2ndary prevention

1. ASA
2. unfractionoated heparin
3. warfarin
4. low molecular weight heparin (not indicated for stroke prophylaxis)
5. fondaparinux: 
6. clopidogrel not indicated but guideline note specific use in certain circumstances.
7. dabigatran
8. rivaroxaban

Warfarin Key Facts:

MOA

generally occurs 24 hours however peak effect may be delayed 72 to 96 hours.

Therefore in patients with thrombosis or at high risk fro thrombosis, initial treatment with warfarin is combined with treatment with a rapidly acting parenteral anticoagulant such as heparin or LMWH until the INR has been in the therapeutic range for at least 2 days

1. warfarin has a boxed warning regarding bleeding risk
2. its peak AC effect may be delayed 72 to 96 hours
3. the close that produces anti coagulation is close to the dose that increases risk for major bleeding (NARROW THERAPEUTIC WINDOW)
4. INR must be carefully monitored during therapy
5. genetic factors can affect its action
6. many drugs, certain foods and herbal supplements can increase or decrease its AC effects.

1. pro drug that is converted to dabigatran a  direct rhombin inhibitor.
2. binds to the active site of thrombin both free and clot bound thrombin. prevents the actions of thrombin that is it prevents thrombin from converting fibrinogen to fibrin from activating factors V, VII and XI and from stimulating platelets.

CRCL > 30 ml/min = 150 bid

Severe renal dysfunction : CRCL 15 to 30 = 75mg bid

Patients with CrCL < 15 or on dialysis = no recommendations are provided

Moderate renal impairment crcl 30 - 50 with concomitant use of the p-glycoprotein (p-gp) inhibitor dronedarone (an AAD) or systemic ketoconazole == can be expected to produce dabigatran exposure similar to that seen in severe renal impairment and consideration should be given to reducting the dose to 75MG BID.

RELy

what is it?

what were the doses studied?

what were efficacy results?

key clinical trial for dabigatran

compares 150 and 110 prad with warf.

significantly reduced primary endpoint of stroke and systemic embolism relative to warfarin

Prad 150 (2.2%), warf 3.4% prad 110 3.0%

                              Dab 150               warf

ICH                          .3%                      .8%

Life Threatening     1.5%                   1.9%

Major Bleed             3.3%                 3.6%

Major GI                  1.6%                 1.1%

Any GI Bleed            6.1%                 4.1%

any bleed                 16.6%               18.4% 

ADVERSE GI EVENTS in RELY

35% vs 24%

discontinuation 2.1% vs 0.6%

1. Rivaroxaban (Xarelto) MOA

1. binds directly to free factor Xa at the factor Xa active site which prevents prothrombin from being converted to thrombin
2. also binds to Xa that is bound to the prothrombinase complex which prevents clot-associated factor Xa fom converting prothrombin to thrombin

orally QD with evening meal.

renal adjustments:

crcl>50 20 mg qd

crcl 15 to 50 = 15 mg qd

crcl <15 = avoid use

Non Inferior to warfarin in terms of composite endpoint of stroke or non-CNS systemic embolism but superiority to warfarin was not demonstrated.  

***pi states that there is insufficient experience to dtetermine how rivaroxaban and warfarin compare when warfarin therapy is well controlled.

major 3.6 vs 3.5

bleeding into critical organ 0.8 vs 1.2

fatal bleeding 0.2 vs 0.5

bleeding requiring transfusion >2 whole units of blood: 1.7 vs 1.3

GI 2.0 vs 1.2

most common bleeding: 4.3 vs 3.1 

discontinuation similar