Intensity Of Oral Anticoagulant Therapy Research Articles

Low-Intensity International Normalized Ratio (INR) Oral Anticoagulant Therapy in Chinese Patients with Mechanical Heart Valve Prostheses

The purpose of this study was to define the optimal international normalized ratio (INR) intensity of oral anticoagulant therapy in Chinese patients with valve replacement surgery. We studied 1,658 patients who underwent mechanical valve replacement in Beijing Anzhen Hospital; the focus of the study was on correlation between intensity of anticoagulant therapy and thromboembolism/hemorrhage complications. We further followed up 1,508 patients for 46 ± 16 months (range 1-61 months). Average INR was 2.13 ± 0.56, and warfarin dose was 3.09 ± 0.85 mg/day. The incidence rate of anticoagulation-related thromboembolism was 1.17 per 100 patient-years (%/pt-y), and the incidence rate of anticoagulation-related hemorrhage was 2.02%/pt-y. The incidence rate of total complications (i.e., combined thromboembolism and hemorrhages) was 3.24%/pt-y. The rate of total complications in group on INR 1.3-2.3 (aortic valve replacement: 1.3-1.8; mitral valve replacement and double valve replacement: 1.8-2.3) was the lowest among all anticoagulant therapy regimens followed. In conclusion, the relatively low anticoagulant strategy presented above efficiently prevents thrombosis and hemorrhage complications.

LOWERing the INtensity of oral anticoaGulant Therapy in patients with bileaflet mechanical aortic valve replacement: Results from the “LOWERING-IT” Trial

Moderate anticoagulation after mechanical heart valve replacement has been proposed to reduce the risk of bleeding related to lifelong anticoagulation. However, the efficacy of such reduced antithrombotic regimens is still unknown. The present prospective open-label, single-center, randomized controlled trial aimed to evaluate the safety and feasibility of reduced oral anticoagulation after isolated mechanical aortic valve replacement. Low-risk patients undergoing bileaflet mechanical aortic valve replacement were randomized to a low International normalized ratio (INR) target (1.5-2.5; LOW-INR group) or to the standard currently recommended INR (2.0-3.0; CONVENTIONAL-INR group) through daily coumarine oral therapy. No aspirin was added. Median follow-up was 5.6 years. The primary outcome was assessment of noninferiority of the low over the standard anticoagulation regimen on thromboembolic events. Secondary end point was the superiority of the reduced INR target strategy on bleeding events. We analyzed 396 patients (197 in the LOW-INR group and 199 in the CONVENTIONAL-INR group). The mean of INR was 1.94 +/- 0.21 and 2.61 +/- 0.25 in the LOW-INR and CONVENTIONAL-INR groups, respectively (P < .001). One versus three thromboembolic events occurred in the LOW-INR and CONVENTIONAL-INR, respectively, meeting the noninferiority criterion (P = .62). Total hemorrhagic events occurred in 6 patients in the LOW-INR group and in 16 patients in the CONVENTIONAL-INR group (P = .04). LOWERING-IT trial established that the proposed LOW-INR target is safe and feasible in low-risk patients after bileaflet aortic mechanical valve replacement. It results in similar thrombotic events and in a significant reduction of bleeding occurrence when compared to the conventional anticoagulation regimen.

A Replacement for Warfarin

Vitamin K antagonists (VKAs) such as warfarin are the only oral anticoagulants currently available for clinical use. Warfarin has numerous limitations, including slow onset and offset of action, a narrow therapeutic window, and a metabolism that is affected by diet, drugs, and genetic polymorphisms.1 Because of its unpredictable dose response, warfarin requires careful coagulation monitoring to ensure that a therapeutic anticoagulant effect is achieved.2 Variable dose requirements, concern about the risk of bleeding, and the need for frequent coagulation monitoring have prompted the development of new oral anticoagulants to replace warfarin. With a predictable anticoagulant response and little potential for food or drug interactions, these new agents have been designed to be administered in fixed doses without coagulation monitoring. Consequently, these drugs have the potential to simplify long-term anticoagulant therapy. Article p 180 The features of the new oral anticoagulants in the most advanced stages of clinical development are listed in the Table and are compared with those of warfarin. Unlike warfarin, which reduces the functional levels of factors II (prothrombin), VII, IX, and X, these novel agents are directed against the active site of factor Xa or thrombin, the enzymes responsible for thrombin generation and fibrin formation, respectively (see the Figure). Rivaroxaban and apixaban target factor Xa, whereas dabigatran etexilate inhibits thrombin. View this table: Comparison of Warfarin to New Oral Anticoagulants in Advanced Stages of Clinical Development Targets of new oral anticoagulant drugs. Oral factor Xa inhibitors (rivaroxaban, apixaban) bind directly to factor Xa and prevent thrombin generation. Dabigatran etexilate, an orally active direct thrombin inhibitor, undergoes metabolic activation to dabigatran, which binds to the active site of thrombin (factor IIa) and blocks its capacity to convert fibrinogen to fibrin, to activate platelets, and to amplify its own generation by activating factors V, VIII, and XI. By blocking the …

Optimal intensity of oral anti-coagulant therapy in patients with mechanical heart valves

Optimal intensity of oral anti-coagulant therapy in patients with mechanical heart valves

Oral anticoagulation for cerebral ischemia of arterial origin: high initial bleeding risk.

The use of oral anticoagulant therapy for the prevention of arterial thromboembolism in patients who have had ischemic stroke is controversial. Coumarins may increase the bleeding risk in patients with cerebral ischemia of arterial origin. 1) To calculate incidence rates of bleeding and thromboembolic events in patients with noncardiac cerebral ischemia who were treated routinely in an anticoagulation clinic. 2) To assess which factors contribute to the occurrence of events. 3) To determine the optimal intensity of oral anticoagulant therapy in these patients. The authors studied all patients treated for noncardiac cerebral ischemia at the Leiden anticoagulation clinic between 1993 and 1998. Outcome events were major hemorrhage, major arterial thromboembolism, and death. The authors observed 356 patients for 644 patient-years. The incidence of major hemorrhage was 3.9 per 100 patient-years (95% CI, 2.5 to 5.7) and that of thromboembolism was 3.0 per 100 patient-years (95% CI, 1.8 to 4.6). The incidence of hemorrhage varied with the duration of treatment (relative risk [RR] of the first versus the second half-year, 3.8; 95% CI, 1.9 to 7.6), age (RR for age >65 years, 3.7; 95% CI, 1.1 to 12.3), and the intensity of oral anticoagulation (RR, 1.8 for each 0.5 international normalized ratio [INR] unit increase; 95% CI, 1.5 to 2.3). The optimal intensity of oral anticoagulant therapy was 2.5 to 3.5 INR; the best target value was 3.0 INR. The risk of hemorrhage with anticoagulant therapy is high in patients with ischemic stroke of arterial origin but is mainly confined to early use and elderly patients.

Managing Oral Anticoagulant Therapy

S everal important developments in the last 2 decades have improved clinical outcomes with oral anticoagulation therapy and have led to an appropriate increase in the use of this therapy by improving its safety. These developments include defining the appropriate indications for oral anticoagulation through the results of large randomized trials, 1,2 identifying the optimal therapeutic range and reporting format (ie, international normalized ratio [INR]) to maximize safety and effectiveness, 3‐16 and managing the dose of therapy to achieve the maximal time in therapeutic range (TTR). 17‐19 The intensity of therapy and the TTR are two of the most important determinants of therapeutic effectiveness and of reducing hemorrhagic risk. Ideally, the INR should be kept in the therapeutic range most of the time, but many factors influence the attainment of this goal. These include physiologic and pharmacologic factors, such as interacting drugs or illnesses that affect the pharmacokinetics or pharmacodynamics of warfarin, dietary or GI factors that affect the availability of vitamin K1, or physiologic factors that affect the synthetic or metabolic fate of the vitamin K-dependent coagulation factors. Patient-specific factors such as adherence to a therapeutic plan are also important. Last, the physician’s ability to make appropriate dosing and follow-up decisions will have a profound impact, if such decisions are incorrect. The comprehensive management of these variables requires a knowledgeable provider, an organized system of follow-up, reliable prothrombin time (PT) monitoring, and good patient communication and education. This article focuses on dosing management and models of care, and it reviews the evidence that indicates that an organized approach to anticoagulant management leads to better outcomes.

The Effects of Low-intensity Warfarin on Coagulation Activation in Patients with Antiphospholipid Antibodies and Systemic Lupus Erythematosus

The optimal intensity of oral anticoagulant therapy for the prevention of thromboembolism in patients with antiphospholipid antibodies (APLA) and systemic lupus erythematosus is controversial. Retrospective studies have suggested that patients with APLA are resistant to oral anticoagulant therapy, with a targeted International Normalization Ratio (INR) of 2.0 to 3.0, and that a higher intensity of anticoagulation (INR: 2.6 to 4.5) is required to prevent recurrent thromboembolism. To investigate if patients with APLA are resistant to the anticoagulant effect of low intensities of warfarin therapy, we performed a randomized trial in which 21 patients with APLA and systemic lupus erythematosus were allocated to receive one of three intensities of warfarin (INR: 1.1 to 1.4, 1.5 to 1.9 or 2.0 to 2.5) or placebo for four months. The main outcome was the effect of each intensity of warfarin therapy on prothrombin fragment 1+2 level (F1+2), that was used as a marker of coagulation activation. When F1+2 levels in patients allocated to the three warfarin intensities were compared to F1+2 levels in the placebo group, there was a statistically significant decrease (p<0.05) in the patient group receiving warfarin with a targeted INR of 2.0 to 2.5 at two, three and four months, and in the patient group with a targeted of INR 1.5 to 1.9 at three months. We conclude that in patients with APLA and systemic lupus erythematosus, warfarin therapy, with a targeted INR of 2.0 to 2.5, is effective in suppressing coagulation activation, and therefore, might be effective in preventing thromboembolism.

High intensity of oral anticoagulant therapy in patients with cerebral haemorrhage: cause or consequence of the bleeding?

In assessing the optimal intensity of anticoagulant therapy, the International Normalized Ratio (INR) at admission is used as a basis for INR-specific incidence rates. In 47 patients suffering a haemorrhagic stroke we tested the assumption that the INR at admission is an acceptable measure for the INR that preceded the haemorrhage. We found high D-dimer levels in 70% of the patients, which indicated activated coagulation and fibrinolysis. This was not of such an extent that it could also be measured with other routine coagulation tests, with the possible exception of two patients. We found normal INRs in 33 non-anticoagulated patients, and only a mildly prolonged INR of 1.9 in one patient, which was most probably caused by a vitamin K deficiency. We concluded that the INR at admission can be used in studies to assess the optimal level of anticoagulation.

Optimal intensity of oral anticoagulant therapy after myocardial infarction: Aida J. Azar, Suzanne C. Cannegieter, Jaap W. Deckers, Ernest Briët, Paul F.M.M. van Bergen, Jan j.C. Jonker, Frits R. Rosendaal. Rotterdam, Leiden, The Netherlands. J Am Coll Cardiol 1996;27:1349–55

Optimal intensity of oral anticoagulant therapy after myocardial infarction: Aida J. Azar, Suzanne C. Cannegieter, Jaap W. Deckers, Ernest Briët, Paul F.M.M. van Bergen, Jan j.C. Jonker, Frits R. Rosendaal. Rotterdam, Leiden, The Netherlands. J Am Coll Cardiol 1996;27:1349–55

Optimal intensity of oral anticoagulant therapy after myocardial infarction

Objectives.This study attempted to determine the optimal intensity of anticoagulant therapy in patients after myocardial infarction.Background.Treatment with oral anticoagulant therapy entails a delicate balance between over- (risk of bleeding) and under-anticoagulant (risk of thromboemboli). The optimal intensity required to prevent the occurrence of either event (bleeding or thromboembolic) is not known.Methods.A method was used to determine the optimal intensity of anticoagulant therapy by calculating incidence rates for either event associated with a specific international normalized ratio. The numerator included events occurring at given international normalized ratios, and the denominator comprised the total observation time.Results.The study population included 3,404 myocardial infarction patients enrolled in the ASPECT (anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis) trial. Total treatment was 6,918 patient-years. Major bleeding occurred in 57 patients (0.8/100 patient-years), and thromboembolic complications in 397 (5.7/100 patient-years). The incidence of the combined outcome (bleeding or thromboembolic complications) with international normalized ratio < 2 was 8.0/100 patient-years (283 events in 3,559 patient-years), with international normalized ratios between 2 and 3, 3.9/100 patient-years (33 events in 838 patient-years); 3.2/100 patient-years (57 events in 1,775 patient-years) for international normalized ratios between 3 and 4; 6.6/100 patient-years (37 events in 564 patient-years) for international normalized ratios between 4 and 5; and 7.7/100 patient-years (14 events in 182 patient-years) for international normalized ratios >5. After adjustment for achieved international normalized ratio levels, significant predictors were higher levels of systolic blood pressure and age.Conclusions.If equal weight is given to hemorrhagic and thromboembolic complications, these results suggest that the optimal intensity of long-term anticoagulant therapy for myocardial infarction patients lies between 2.0 and 4.0 international normalized ratio, with a trend to suggest an optimal intensity of 3.0 to 4.0.

Optimal Oral Anticoagulant Therapy in Patients with Nonrheumatic Atrial Fibrillation and Recent Cerebral Ischemia

A number of studies have demonstrated the efficacy of oral anticoagulant therapy in reducing the risk of stroke and systemic embolism in patients with nonrheumatic atrial fibrillation. However, both the targeted and the actual levels of anticoagulation differed widely among the studies, and a number of studies failed to report standardized prothrombin-time ratios as international normalized ratios (INRs). We therefore performed an analysis to determine the intensity of oral anticoagulant therapy in nonrheumatic atrial fibrillation that provides the best balance between the prevention of thromboembolism and the occurrence of bleeding complications. We calculated INR-specific incidence rates for both ischemic and major hemorrhagic events occurring in 214 patients who received anticoagulant therapy in the European Atrial Fibrillation Trial, a secondary-prevention trial in patients with nonrheumatic atrial fibrillation and a recent episode of minor cerebral ischemia. The optimal intensity of anticoagulation was found to lie between an INR of 2.0 and an INR of 3.9. No treatment effect was apparent with anticoagulation below an INR of 2.0. The rate of thromboembolic events was lowest at INRs from 2.0 to 3.9, and most major bleeding complications occurred with treatment at intensities with INRs of 5.0 or above. To achieve optimal levels of anticoagulation with the lowest risk in patients with atrial fibrillation and a recent episode of cerebral ischemia, the target value for the INR should be set at 3.0, and values below 2.0 and above 5.0 should be avoided.

Optimal oral anticoagulant therapy in patients with mechanical heart valves.

The optimal intensity of oral anticoagulant therapy for patients with mechanical heart valves (i.e., the level at which thromboembolic complications are effectively prevented without excessive bleeding) is not known. We attempted to determine the optimal intensity by calculating the incidence of both complications at different levels of anticoagulation. Data were collected on all patients with mechanical heart valves who have been seen at four regional Dutch anticoagulation clinics since 1985. The primary outcome events were episodes of thromboembolism or major bleeding. The intensity-specific incidence of each type of event was calculated as the number of events that occurred at a certain intensity of anticoagulation (expressed in terms of the international normalized ratio [INR]) divided by the number of patient-years during which the INR was at this level in the total patient population. A total of 1608 patients were followed during 6475 patient-years. Cerebral embolism occurred in 43 patients (0.68 per 100 patient-years) and peripheral embolism in 2 (0.03 per 100 patient-years). Intracranial and spinal bleeding occurred in 36 patients (0.57 per 100 patient-years) and major extracranial bleeding in 128 (2.1 per 100 patient-years). The optimal intensity of anticoagulation, at which the incidence of both complications was lowest, was achieved when the INR was between 2.5 and 4.9. The intensity of anticoagulant therapy for patients with prosthetic heart valves is optimal when the INR is between 2.5 and 4.9. To achieve this level of anticoagulation, a target INR of 3.0 to 4.0 is recommended.

A Method to Determine the Optimal Intensity of Oral Anticoagulant Therapy

Oral anticoagulant therapy has been shown to be effective for several indications. The optimal intensity of anticoagulation for each indication, however, is largely unknown. To determine this optimal intensity, randomised clinical trials are conducted in which two target levels of anticoagulation are compared. This approach is inefficient, since the choice of the target levels will be arbitrary. Moreover, the achieved intensity is not taken into account. We propose a method to determine the optimal achieved intensity of anticoagulation. This method can be applied within a clinical trial as an "efficacy-analysis", but also on data gathered in day-to-day patient care. In this method, INR-specific incidence rates of events, either thromboembolic or hemorrhagic, are calculated. The numerator of the incidence rate is based on data on the INR at the time of the event. The denominator consists of the person-time at each INR value, summed over all patients, and is calculated from all INR measurements of all patients during the follow-up interval. This INR-specific person-time is calculated with the assumption of a linear increase or decrease between two consecutive INR determinations. Since the incidence rates may be substratified on covariates, efficient assessment of the effects of other factors (e.g. age, sex, comedication) by multivariate regression analysis becomes possible. This method allows the determination of the optimal pharmacological effects of anticoagulation, which can form a rational starting point for choosing the target levels in subsequent clinical trials.