Oral Anticoagulants

Oral anticoagulants: Pharmacologic issues for use in the elderly

Several studies have shown that in patients treated with vitamin K antagonists (VKAs) time spent in therapeutic range (TTR) is lower in females than in males. This retrospective study has evaluated a possible association among over-anticoagulation and gender, type and indications to VKAs, TTR and bleeding. Moreover, the decrease of the INR level, after VKAs withdrawal, was considered.

From December 2020 to January 2004, 1230 patients with venous thromboembolism or atrial fibrillation were enrolled. Age, gender, type of VKAs, clinical indications, INR values and bleeding events were recorded. TTR was calculated considering the entire period of treatment.

A total of 1616 and 1759 over-anticoagulation episodes were found in males and females, respectively. The median INR value was 4.5 (4.0–19.04). Thirty-two percent of the patients did not have an overdose throughout the observation period. The median number of over-anticoagulation per year was significantly higher in females (0.39-year) than in males (0.28-year). After 24 h of VKAs withdrawal, INRs were similar in both genders. Logistic regression analysis showed that the episodes of over-anticoagulation per year were associated with females, atrial fibrillation, warfarin therapy, follow-up length longer than 4 years, and TTR <73%, but were not associated to bleeding episodes.

The higher number of over-anticoagulation can explain the lower TTR in females. An excess of anticoagulation is not associated with bleeding events. The recovery of INR performs better when acenocoumarol is used, therefore, in patients who present several episodes of over-anticoagulation, acenocumarolo could replace warfarin.

Warfarin doses are greatly affected by polymorphism altering cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) gene. This study evaluated the prevalence of alleles (either single or double) and carriers of single nucleotide polymorphisms (SNPs) in both genotypes CYP2C9 and VKORC1 in alkharj area, Saudi Arabia and its association with warfarin use risk. Total 112 samples were collected and genotyped using FlexiGene DNA Kit for isolation and StepOnePlus Real-Time PCR System by TaqMan allelic discrimination methods. The results indicated the frequency of 11%, 8% and 45% for CYP2C9 *2 *3 and VKORC1-1639 G > A polymorphism. And as a combination genotype it was 15.18% For both CYP2C9 and VKORC1 polymorphism, 27.67% for CYP2C9 and 42.86% for VKORC1. Non-carriers rate came to be at 30.3%. According to previously published dosing changes in warfarin for polymorphism carriers (single-double-triple). The predicted warfarin doses reduction in order of 1–1.6, 2–2.9, 2.9–3.7 mg/day. It was found that 72.3% of the study population was carrier of a type of polymorphism, 15.18% for two types of polymorphisms. These findings predict changes in warfarin metabolism and eventually dosing alteration among patients on warfarin. Both genotypes (CYP2C9 and VKORC1) require different dosing of warfarin than non-carriers in order to minimize the risk of warfarin overdosing and avoidance of the drug-related problems (DRPs).

The use of anticoagulants in patients with cancer is challenging as several co-morbidities modifying pharmacokinetic (PK) parameters and significant drug-drug interactions with concomitant anti-neoplastic therapies may lead to PK variability resulting in increased risk of thrombosis or bleeding.

Data on the management of patients with cancer-associated thrombosis (CAT) in real life are scarce since patients with cancer presenting with significant comorbidities tend to be excluded from large trials.

This review is mostly based on case-reports and pharmacokinetics in an attempt to provide oncologists, with relevant orientation based on our best knowledge to date.

Overall, low-molecular-weight heparins (LMWH) are the preferred option for the long-term prophylaxis and treatment of CAT as their benefit-risk was shown superior to vitamin K antagonists (VKA). Direct oral anticoagulants (DOAC) may represent an alternative to LMWH provided that a favorable benefit-risk in patients with CAT is evidenced in the future. We recommend a systematic risk-assessment including body composition, multiple medication, and renal function. Moreover a systematic and early discussion between pharmacist and oncologist should optimize the benefit-risk ratio for each patient.

Atrial fibrillation (AF) is a particularly prevalent and challenging to manage disease in the elderly. This study aims to evaluate the adequacy of ESC guidelines for the management of AF in a clinical setting with an aged population.

Retrospective study of 212 hospitalizations with a diagnosis of AF. Patients admitted to the unit from January to June of 2012 were eligible for the study; their clinical status, underlying morbidities, and AF treatments were assessed.

The mean age of the study population was 78.6 ± 10.2 years old; more than 90% of the cases were ≥ 65 years old. Permanent AF was the most frequent form of the disease (66.0%), followed by paroxysmal AF (24.1%). Infection was the leading reason for hospitalization (39.2% of cases); AF (or flutter) was the reason for hospitalization in 15.6% of cases. Rate and/or rhythm control therapy was administered in 40.6% of cases at the emergency department and in 75.0% of cases at discharge; amiodarone was the most used drug in all clinical scenarios. At admission, anticoagulation therapy was not being used in 64.1% of cases; at discharge (57.2%). The main reason for non-anticoagulation was HAS-BLED ≥ 3 (60%); in 23.5% of the cases there was no explicit reason for non-anticoagulation.

The elderly population with AF presents some distinctive characteristics that the current ESC guidelines do not consistently address. There is a need to develop guidelines tailored to the elderly population, allowing the use of validated, systematic treatment approaches in this highly relevant population.

The multiple organ dysfunction syndrome (MODS) is characterized by more than one organ system failing, especially during critical illness. MODS is the leading cause of morbidity and mortality in current ICU practice; moreover, multiple organ dysfunction, especially liver and kidneys, may significantly affect the pharmacokinetics (PKs) of different drugs that are currently administered in critically ill patients. These PK alterations may either result in insufficient drug concentrations to achieve the desired effects or in blood and tissue accumulation, with the development of serious adverse events. The use of extra-corporeal circuits, such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), may further contribute to PKs changes in this patients' population. In this review, we have described the main PK changes occurring in all these conditions and how drug concentrations may potentially be affected. The lack of prospective studies on large cohorts of patients makes impossible any specific recommendation on drug regimen adjustment in ICU patients. Nevertheless, the clinicians should be aware of these abnormalities in order to better understand some unexpected therapeutic issues occurring in such patients.

Reversal of overanticoagulation to minimize the bleeding risk is important in elderly inpatients receiving vitamin K antagonist therapy. However, no study has specifically focused on this population. The objective of this study is to evaluate whether guidelines based on American College of Chest Physicians recommendations for the management of overanticoagulation (international normalized ratio [INR] ≥5.0) can apply to elderly inpatients, and notably allow 24-hour INRs to return to the 1.8-3.2 range in this population. The influence of different factors on the vitamin K response also was evaluated.

Inpatients aged ≥75 years with INR ≥5.0 were included in this observational study. INRs were assessed on the day of the overdosage (Day 0) and on the following day (Day 1).

Of 385 Day 0 INRs ≥5.0 (239 patients; 86 ± 6 years), 217 were managed according to recommendations, with a mean INR decreasing from 6.8 ± 2.4 (range: 5.0-20.0) on Day 0 to 2.7 ± 1.3 (range: 1.1-10.1) on Day 1 (P < .0001); 55% of INRs were within the 1.8-3.2 range, 20% <1.8, and 25% >3.2. In the subset of Day 0 INRs between 5.0 and 6.0, mean INR decreased from 5.5 ± 0.3 to 2.7 ± 1.0 (P < .0001) on Day 1 after oral administration of 1 mg vitamin K1 (n = 121) and from 5.3 ± 0.3 to 5.0 ± 1.6 (P = .149) without vitamin K1 administration (n = 48). Among covariates entered in the multivariate analysis, including co-medications, only the vitamin K1 dose influenced Day 1 INRs, with higher doses of vitamin K1 associated with Day 1 INRs <1.8 (P < .0001).

In elderly inpatients with INR ≥5.0, both vitamin K antagonist dose omission and vitamin K1 administration according to recommendations were effective in reversing overanticoagulation, allowing most INRs to return to the 1.8-3.2 range without excessive overcorrection. Therefore, American College of Chest Physicians recommendations may be applied to elderly inpatients.