*2.1.2. Acenocoumarol and phenprocoumon*

unstable. After INR stabilization, clinicians should adopt a maintenance dosing. The weekly dose can be prescribed using a range of dosing regimens (i.e., alternate day dosing or dose

• INR between 1.5 and 1.9: weekly dose should be increased by 10% only if the alteration of

• INR between 3.1 and 3.9: weekly dose should be decreased by 10–20% only if the alteration

• INR between 4 and 4.9: the patient has to omit one dose, decrease the weekly dose by

For INR values greater than or equal to 5, there is a significantly increased risk of bleeding and vitamin K administration should be evaluated. Patients have to cease warfarin therapy and

In case of switch to another anticoagulant agent and in particular to a direct oral anticoagulant agents (DOACs) in patients with atrial fibrillation, INR should be strictly monitored. Apixaban and dabigatran should be started when INR < 2, rivaroxaban when INR < 3, and

Vitamin K antagonists reduce stroke and systemic embolism by 64% and all-cause mortality by 26%, compared to placebo in patients with atrial fibrillation [21]. However, as already mentioned above, VKAs have many drug and food interactions and require routine INR monitoring, and these limitations result in under-treatment for 30–50% of AF patients [22].

DS2

stroke risk factors in everyday clinical practice and has been validated in multiple cohorts;

DS2

tifying patients who develop stroke and thromboembolism [24]. Direct comparison between the effects of warfarin and aspirin has been undertaken in several studies, demonstrating that warfarin was significantly superior, with a relative risk (RR) reduction of stroke of 39%. In clinical practice, the risk of stroke should be weighed against the risk of bleeding to assess appropriateness of anticoagulant therapy. Warfarin causes major bleedings in 1–2% of people treated and intracranial bleeding in 0.1–0.5% of patients each year of treatment [25]. The highest rate of major

patients with AF and is as good as, and possibly better than, scores such as CHADS2

by a factor of 1.5. Treatment with warfarin is recommended for a CHADS2

scores of equal to or greater than 2. While the CHADS2

many common stroke risk factors. The CHA2

the accumulated evidence shows that CHA2

scoring system [23] is a simple system that can be used to assess the annual risk

scoring system, each point increases the annual risk of stroke

or CHA2

score is simple, it does not include

VASc score is inclusive of the most common

VASc is better at identifying "truly low-risk"

DS2

VASc

in iden-

regimens with different doses for weekdays compared to the weekend).

• INR < 1.5: weekly dose should be increased by 20%;

• INR between 2 and 3: no change in dose regimen;

restart with a reduced dose, when INR is minor than 5 [19].

of the values persists for more than a week;

10–20%, and monitor INR in 2–5 days.

edoxaban when INR ≤ 2.5 [20].

*2.1.1.6. Real-world safety aspects*

of stroke in AF. In the CHADS2

The CHADS2

86 Anticoagulant Drugs

the values persists for more than a week;

Dose modification should be taken into account following the INR monitoring:

Like warfarin, acenocoumarol and phenprocoumon also exist as optical isomers that have different stereochemical characteristics. R-acenocoumarol has an elimination half-life of 9 h; it is primarily metabolized by CYP2C9 and CYP2C19 and is more potent than S-acenocoumarol. In fact, S-acenocoumarol has a faster clearance (elimination half-life of 0.5 h), it is primarily metabolized by CYP2C9 and undergoes extensive first pass metabolism. The treatment dose may vary between patients up to 10-fold, ranging from 1 to 9 mg daily [28, 29].

Phenprocoumon is a much longer acting agent, with both the R- and the S-isomers with elimination half-lives of 5.5 days. Both are metabolized by CYP2C9, and S-phenprocoumon is 1.5–2.5 times more potent than R-phenprocoumon. It is administered in daily maintenance doses of 0.75–9 mg [29, 30].

As for warfarin, allelic variants of CYP2C9, CYP2C9\*2, and CYP2C9\*3 could lead to bleeding complications, especially if they code for enzymes with approximately 12 and 5% of the enzymatic activity of the wild type genotype CYP2C9\*1 [31].
