Bayer Pharma AG

November Issue - Novel oral anticoagulants in different thromboembolic indications: tailored doses and regimens provide physicians with the confidence to treat

Professor Reinhold Kreutz, MD

Reinhold Kreutz is Professor of Clinical Pharmacology and Internal Medicine at the Centre for Therapeutic Research, Charité University Hospital, Berlin, Germany. He completed his medical education and began his scientific research in both Germany and the USA. Professor Kreutz is a Fellow of the American Heart Association (AHA), a member of the European Society of Hypertension (ESH) and the European Council for Blood Pressure and Cardiovascular Research, and is serving on the Guidelines Committee for Drug Treatment of the German Hypertension Society. His clinical focus is arterial hypertension, clinical pharmacology, and drug treatment in the elderly, and his research interests centre on the genomics and pharmacogenomics of arterial hypertension and related diseases.

Welcome to the November 2015 edition of the Thrombosis Adviser newsletter.

Dear Ladies and Gentlemen,

The optimal use of all drug treatments is based on a balance of efficacy (benefit) and safety (risk). In determining the appropriate dose and regimen of any drug, several factors must be taken into account, including the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug, the pathophysiology of the target disease, the characteristics of the patient populations being treated, and (most importantly) the observed efficacy and safety outcomes in clinical studies. In addition, simple methods of administration and convenient dosing schedules are helpful to patients and encourage adherence to therapy.

In the case of anticoagulants, the benefit–risk balance primarily concerns antithrombotic efficacy versus bleeding complications. Traditional anticoagulants, heparins and vitamin K antagonists (VKAs), have very different PK/PD characteristics. Heparins are fast-acting drugs with a relatively short half-life and, for low molecular weight heparins at least, an anticoagulant effect (PD) that is closely linked to dose (PK). This means that their antithrombotic effect can be quickly ‘switched’ on and off, which is advantageous for acute treatment and in the event of bleeding complications, but the requirement for parenteral administration limits their long-term use. For long-term anticoagulation, therefore, oral VKAs have generally been preferred. However, VKAs are characterized by a non-linear PK/PD relationship and a mechanism of action that results in a slow onset and offset of action after dosing starts and stops, respectively. In addition, VKAs exhibit considerable interindividual variability in their dose–response relationship. VKAs are also further subject to a number of clinically relevant interactions with common co-medications and foods, meaning that fixed dosing is not possible; patients are instead subject to regular coagulation monitoring (using international normalized ratio) and dose adjustments. For these reasons, in many patients maintaining a therapeutic level of anticoagulation is challenging.

The non-VKA oral anticoagulants (NOACs) were developed to provide a linear and predictable PK/PD profile with the convenience of oral dosing, using fixed doses for broad populations without inconvenient routine coagulation monitoring and with fewer drug interactions than VKAs. The NOACs are small molecules that directly inhibit a single coagulation factor (Factor Xa in the case of apixaban, edoxaban and rivaroxaban, and Factor IIa [thrombin] for dabigatran). All of these drugs have anticoagulant effects that are closely linked to dose and plasma drug levels. The half-lives of the NOACs (up to approximately 15 hours) would suggest that these drugs should be dosed twice daily in order to maintain antithrombotic efficacy. However, this is not uniformly true because there are other factors that need to be taken into account when choosing the optimal dose regimens.

When selecting an appropriate anticoagulant, patient preference and circumstances, as well as likely or actual therapeutic adherence, should be taken into account. In the treatment of VTE, for example, using a single oral drug from the start of therapy, as is the case with apixaban and rivaroxaban, may provide advantages for both patients and physicians in the management of the disease. On the other hand, if oral treatment is not appropriate at the start of therapy (e.g. in a patient unable to swallow or vomiting), initial parenteral anticoagulation followed by transitioning to any NOAC is a reasonable alternative approach. For long-term treatment, several studies indicate that patients are more likely to adhere better to a once-daily treatment schedule than to therapies dosed more frequently. Ultimately, decisions on the selection of NOAC and on once- versus twice-daily dosing approaches will be based on a variety of factors related to the patient’s individual circumstances. However, physicians choosing to prescribe a NOAC can be reassured that the approved dosing schedules of these agents have been devised based on a logical, empirical and pharmacological approach, and that these doses have been tested rigorously in large, randomized phase III studies.

Yours sincerely,

Reinhold Kreutz
Berlin, Germany

First, the magnitude of antithrombotic effect appropriate to the thromboembolic disease must be considered. For example, the total daily dose needed for the primary prevention of venous thromboembolism (VTE) after major orthopaedic surgery would be expected to be lower than that required for prevention of recurrence in a patient who has already had a first VTE. For the acute treatment of VTE, a still greater anticoagulant effect is desirable. For patients with atrial fibrillation (AF), it is well established that the strength of anticoagulation needed to prevent the severe consequences of AF-related complications, i.e. stroke and systemic embolism, is similar to that needed for long-term secondary prevention in patients with VTE. A lower intensity of anticoagulation is likely to be appropriate for secondary prevention of cardiovascular events in patients who have had a recent acute coronary syndrome, because of an increased risk of bleeding when anticoagulation is added on top of standard antiplatelet therapy.

Second, it is necessary to understand how once-daily and twice-daily dosing affects the minimum (Ctrough) and maximum (Cmax) plasma drug concentrations, which would be expected to correlate with bleeding risk (Cmax) and thrombotic risk (Ctrough) in drugs such as the NOACs, which have linear PK/PD relationships. Once-daily dosing is normally associated with higher Cmax and lower Ctrough levels than twice-daily dosing, which might suggest a higher risk of both bleeding and thrombosis for a once-daily dosing regimen. Based on these considerations, it would appear reasonable to develop twice-daily dosing approaches in indications such as VTE treatment and stroke prevention in AF, when a relatively high intensity of anticoagulation is required. This has been done for apixaban and dabigatran. However, in dose-finding studies and pharmacokinetic modelling in patients with VTE or AF receiving long-term rivaroxaban or edoxaban, once-daily dosing actually indicated a similar or better balance of efficacy and safety than twice-daily regimens for these drugs in these indications. Even so, it was necessary to address the need for a more intensive antithrombotic effect during the acute phase of VTE treatment by the use of initial parenteral anticoagulation with edoxaban, and a twice-daily regimen for the first 21 days of treatment with rivaroxaban. For acute VTE treatment with the other NOACs, dabigatran is given after initial parenteral anticoagulation, whereas an intensive regimen is employed for 7 days with single-drug apixaban.

Third, the total daily dose applied is also a crucial factor affecting the choice between a once-daily and twice-daily dosing approach for NOACs with a mean half-life of about 10–11 hours. Hence, when a low dose range of rivaroxaban treatment was explored in patients with recent acute coronary syndrome and elevated cardiac biomarkers who were also taking background antiplatelet therapy, a twice-daily regimen was found to provide the best balance of efficacy and bleeding risk. Taken together, these examples illustrate the need to consider disease conditions, patient characteristics and pharmacological factors together when determining dosing and dose regimens.

Based on PK/PD data and modelling and dose-finding clinical studies, and confirmed in large, randomized phase III clinical trials, the dose regimens approved in Europe for the novel OACs are shown below. Although NOACs can be given at fixed standard doses in most patients, there are circumstances where dose adjustment is mandated – indicated by lighter coloured circles in the figure. Dose adjustment is based upon PK/PD observations in certain patient groups, such as those with impaired renal function, and taking into account clinically relevant drug interactions. Use of rivaroxaban, apixaban and edoxaban is not recommended in patients with creatinine clearance <15 ml/min, and these agents should be used with caution in patients with severe renal impairment (creatinine clearance 15–29 ml/min). In Europe dabigatran is contraindicated in those with creatinine clearance <30 ml/min.

aApproved after elective hip or knee replacement; btwo capsules of dabigatran 110 mg taken together; ctwo capsules of dabigatran 75 mg taken together for patients with moderate renal impairment (CrCl 30–50 ml/min), patients taking concomitant verapamil, amiodarone, quinidine, or those aged ≥75 years; din phase III trials of VTE treatment, parenteral anticoagulation was used in the acute phase, transitioning to the novel OAC at the same dose as shown in the figure for secondary prevention; epatients aged ≥80 years or those taking concomitant verapamil, plus any patients meeting the following criteria based on individual assessment of the thrombotic and bleeding risk: age 75–80 years, moderate renal impairment (CrCl 30–50 ml/min), gastritis, esophagitis or gastroesophageal reflux, or any other patient at increased risk of bleeding; freduced dose approved for patients with ≥2 of the following: age ≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dl (133 µmol/l); greduced dose approved for patients with moderate/severe renal impairment (CrCl 15–50 ml/min) or body weight ≤60 kg or in those taking the P-glycoprotein inhibitors ciclosporin, dronedarone, erythromycin or ketoconazole; happroved in combination with acetylsalicylic acid with or without clopidogrel or ticlopidine in patients after recent ACS and elevated cardiac biomarkers; ifor patients with moderate or severe renal impairment (CrCl 15–49 ml/min), the rivaroxaban 20 mg od dose is recommended; however, a reduction of the dose from rivaroxaban 20 mg od to 15 mg od should be considered if the patient’s assessed risk for bleeding outweighs the risk for recurrent DVT and/or PE; jpatients with moderate or severe renal impairment (CrCl 15–49 ml/min) receive rivaroxaban 15 mg od. ACS, acute coronary syndrome; AF, atrial fibrillation; bid, twice daily; CrCl; creatinine clearance; DVT, deep vein thrombosis; OAC, oral anticoagulant; od, once daily; PE, pulmonary embolism; VTE, venous thromboembolism.


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