Original Article
Trial of Different Intensities of Anticoagulation in Patients with Prosthetic Heart Valves
N Engl J Med 1990; 322:428-432February 15, 1990
- Abstract
- Abstract
We compared the efficacy and complications of anticoagulation with warfarin in 258 patients with prosthetic heart valves treated with regimens of "moderate intensity" (prothrombin-time ratio, 1.5; international normalized ratio, 2.65) or "high intensity" (prothrombin-time ratio, 2.5; international normalized ratio, 9) in a prospective, randomized study. The two patient groups were followed up for 421 patient-years and 436 patient-years, respectively. Eleven patients were lost to follow-up.
Thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 episodes per 100 patient-years, respectively), but there was a total of 6.2 bleeding episodes per 100 patient-years in the moderate-intensity group, as compared with 12.1 episodes in the high-intensity group (P<0.002). There were 5.2 episodes of minor bleeding per 100 patient-years in the moderate-intensity group, as compared with 10.1 episodes in the high-intensity group (P<0.01). Major bleeding was also more common in the high-intensity group (2.1 episodes per 100 patient-years — including the only two fatal hemorrhages — as compared with 0.95 episode in the moderate-intensity group), but the difference was not statistically significant.
We conclude that a moderate anticoagulant effect (prothrombin-time ratio, about 1.5) in patients with a mechanical prosthetic heart valve offers protection equivalent to that of more intensive therapy, but at a significantly lower risk. (N Engl J Med 1990; 322:428–32.)
Media in This Article
Figure 1
Prothrombin-Time Ratios at Time of Patients' Presentation with Thromboembolic Events.Table 1
Rate of Accession, Number of Patients Assigned to Treatment and Followed up, and Length of Follow-up.Article Activity
- Article
THROMBOSIS affecting prosthetic heart valves and arterial thromboembolism remain major causes of late morbidity and mortality after the replacement of heart valves with mechanical prostheses, despite improvements in valve design.1
Factors that influence the risk of arterial thromboembolism include the type, site, and number of valves replaced,1 2 3 4 5 the presence or absence of atrial fibrillation,6 treatment with warfarin or other oral anticoagulants,1 the adequacy of warfarin therapy, and the addition of antiplatelet drugs such as dipyridamole and aspirin.1
Although a need for lifelong warfarin treatment after the mechanical replacement of valves, particularly in the mitral site (and probably in the aortic site), is now generally accepted, uncertainty remains about its optimal intensity.4 , 7 , 8 Because retrospective surveys strongly suggest that thromboembolism is much more likely when the effect of warfarin is low or absent,7 , 9 10 11 more rather than less intense therapy has usually been recommended. In Europe, therapy usually aims for an international normalized ratio (a system for standardizing the results of prothrombin-time tests performed with different reagents) of 3.0 to 5.0, and in North America it aims for even higher levels,12 although recently there appears to be some agreement on an international normalized ratio of between 3.0 and 4.5 in patients with a mechanical prosthetic valve.13 The question is both important and topical, since the risk of bleeding increases with higher levels of anticoagulation and since randomized studies have shown that secondary prevention after venous thrombosis requires a less intense anticoagulant effect (international normalized ratio, 2.0 to 2.5) than was previously thought.14
We conducted a prospective, open clinical trial in which patients with prosthetic heart valves were randomly assigned to therapy designed to achieve one of two levels of anticoagulant effect: a prothrombin-time ratio (the ratio of the patient's prothrombin time to that of pooled normal plasma) of 1.5 (international normalized ratio, 2.65) or a prothrombin-time ratio of 2.5 (international normalized ratio, 9). These values correspond to the extremes of the accepted therapeutic range in many centers.15 , 16
Methods
Patients
All patients who received mechanical prosthetic valves for rheumatic heart disease and attended the anticoagulation clinic between 1981 and 1985 were randomly assigned to one of two treatment groups, which differed only in the intended level of anticoagulant effect (moderate or high). There were no exclusions. All those enrolled in the study gave their informed consent. Each patient, including those who were later lost to follow-up, was given a consecutive, randomly distributed number at entry. Patients with even and odd numbers constituted the moderate- and high-intensity groups, respectively. Randomization was substratified for the presence or absence of atrial fibrillation. The patients remained in the trial until death or the termination of the study in September 1986.
Prothrombin Time
Blood (nine volumes) was collected in silicon-coated, evacuated glass tubes containing one volume of 3.8 percent sodium citrate (total volume, 4.5 ml) (Vacutainer, Becton Dickinson, Rutherford, N.J.) and platelet-poor plasma separated after centrifugation at 2000×g and 4°C for 10 minutes. The prothrombin time of the platelet-poor plasma was measured with use of Simplastin (General Diagnostics, Morris Plains, N.J.), a rabbit-brain thromboplastin with an international sensitivity index of 2.4, and an automated, optical-end-point, blood-coagulation instrument (Coag-a-mate X2, General Diagnostics).
The results were reported as a prothrombin-time ratio without conversion to an international normalized ratio, and they were available in the anticoagulation clinic when patients were seen for adjustment of their dose of warfarin.
Anticoagulation Therapy
The aim of treatment in the moderate-intensity group was a prothrombin-time ratio of 1.5 (international normalized ratio, 2.65), and the acceptable range was 1.3 to 1.7. In the high-intensity group the target was a ratio of 2.5 (international normalized ratio, 9.0), and the acceptable range was 2.3 to 2.7.
Oral anticoagulant therapy was begun within 10 days of surgery. All the patients were seen at the anticoagulation clinic within one week of discharge, and then every few days until their prothrombin-time ratio stabilized in the intended range. Thereafter, the patients were seen every four weeks, or more frequently if their prothrombin-time ratio was outside the intended range. None were treated initially with antiplatelet drugs. Dipyridamole (75 mg three times a day) was given later to patients who had a thromboembolic episode.
All the patients were advised of the risks of treatment and provided with a pamphlet stressing the adverse effects of warfarin and emphasizing the dangers of drug interaction, particularly with aspirin and other nonsteroidal antiinflammatory drugs. They were also told not to take any unprescribed medication. All the patients were also given a card with a list of their medications, as well as instructions to call the clinic or go to the emergency room if bleeding or symptoms suggestive of a thromboembolic episode developed. A list of the manifestations of thromboembolism or bleeding was included. The patients were told to carry the card at all times and to show it to any doctor who saw them between visits to the clinic.
At the anticoagulation clinic, a record of the prothrombin-time ratio was kept, and bleeding or thromboembolic episodes were also recorded.
A diagnosis of cerebral embolism was accepted for the purposes of the study if there was a residual neurologic deficit and if a computerized tomographic scan of the brain excluded bleeding as a possible cause. Other systemic embolization was confirmed by angiography or surgery. Suspected coronary-artery embolism was confirmed by coronary angiography or by the onset of myocardial infarction as evidenced by typical electrocardiographic changes and elevated levels of cardiac enzymes in a young person with coronary arteries that had been normal on angiography.
Bleeding was considered major if the patient died or required transfusion, hospitalization, or surgery. All other bleeding was defined as minor.
Statistical Analysis
The data were analyzed on a TANDON ATcompatible microcomputer with use of the SOLO statistical software package. The results of logistic-regression analysis were confirmed with use of the BMDP statistical package. The variables investigated were the intensity of anticoagulation, the duration of therapy, and the patient's age, sex, and history of smoking, diabetes, and atrial fibrillation. Because none of the patients had hypertension, it was not included in the final analysis. Relative risks were derived from the logistic-regression coefficient.
Results
Patients
The characteristics of the patient groups are shown in Tables 1Table 1
Rate of Accession, Number of Patients Assigned to Treatment and Followed up, and Length of Follow-up. and 2Table 2
Age and Sex of Patients, Type and Site of Valves, and Prevalence of Atrial Fibrillation.. We randomly assigned 258 patients to the treatment groups, but 11 patients (5 from the moderate-intensity and 6 from the high-intensity group) were lost to follow-up. Our analyses therefore involved 247 patients. All the patients were normotensive on entry and remained so during the follow-up period.Of the 11 patients who were lost to follow-up, 9 were citizens of Yemen, to which they returned six months after their operations. None had had bleeding or thromboembolic episodes. The other two (one from each group) lived in Riyadh but were lost to follow-up seven and nine months after their operations, without any earlier complications.
Dose of Warfarin and Anticoagulant Effect
The mean (±SD) doses of warfarin in the moderate- and high-intensity groups were 5.9±2 and 8.5±2.3 mg, respectively. The anticoagulant effects were within the intended ranges (prothrombin-time ratios, 1.3 to 1.7 and 2.3 to 2.7, respectively) at 86 percent of the visits.
Thromboembolic Episodes and Prothrombin-Time Ratio
There were 33 thromboembolic episodes among the 247 study patients (3.85 per 100 patient-years), 17 in the moderate-intensity group and 16 in the high-intensity group, corresponding to embolism rates of 4.0 and 3.7 episodes per 100 patient-years, respectively. Table 3Table 3
Thromboembolic Episodes in the Two Treatment Groups. shows the 95 percent confidence intervals for the observed incidence of systemic embolism and the sites of thromboembolism. There was no difference in the incidence or relative risk of thromboembolism between the two groups. None of the thromboembolic episodes occurred very early after the insertion of the prosthetic valve — i.e., before proper anticoagulant therapy. One third of the episodes occurred within the first 12 months of therapy.Prothrombin-time ratios measured at the time of the patients' presentation with thromboembolism are shown in Figure 1Figure 1
Prothrombin-Time Ratios at Time of Patients' Presentation with Thromboembolic Events.. The ratio in six patients with systemic embolism (three from each group) was 1.0. All six had discontinued anticoagulant therapy of their own volition before their thromboembolic episode. The prothrombin-time ratio in 12 patients (7 from the moderate-intensity group and 5 from the high-intensity group) was low, between 1.1 and 1.3. Ratios in the remaining 15 patients with thromboembolism ranged between 1.4 and 2.2.Bleeding Episodes, Possible Predisposing Factors, and Prothrombin-Time Ratio
Table 4Table 4
Bleeding Episodes in the Two Treatment Groups. shows the sites of major and minor bleeding episodes in both groups. There were 79 bleeding episodes (9.2 per 100 patient-years); 66 were minor (7.7 per 100 patient-years) and 13 were major (1.5 per 100 patient-years), including 2 fatal episodes of intracranial bleeding.Forty-four minor and nine major episodes of bleeding (including both fatal episodes) occurred in the high-intensity group, which had a significantly greater risk of any bleeding (P<0.002) and of minor bleeding (P<0.01). The trend toward a greater risk of major bleeding was not statistically significant (P>0.05). The relative risk of any bleeding in the high-intensity group as compared with the moderate-intensity group was 2.5 (95 percent confidence interval, 1.4 to 4.4), and of minor bleeding 2.25 (95 percent confidence interval, 1.2 to 4.7).
Five of the 13 patients with major bleeding (including the 2 with fatal intracranial bleeding) had no apparent predisposition other than warfarin therapy, and all 5 were in the high-intensity group. Another four patients (two from each group) had possible predisposing factors for major bleeding: the recent intake of aspirin or a nonsteroidal antiinflammatory drug in three and a possible duodenal ulcer in one. The prothrombin-time ratio was above 3.0 in all nine of these patients. Probable contributing factors in the remaining four patients with major bleeding (two from each treatment group) included local trauma in two, a kidney stone in one, and a renal tumor in one; their prothrombin-time ratios at the time of bleeding were between 1.6 and 2.1.
Discussion
This open, randomized trial compared the incidence of systemic thromboembolism and bleeding complications in patients with mechanical heart-valve prostheses who received warfarin at one of two levels of anticoagulant intensity (moderate prothrombin-time ratio, 1.5, and high prothrombin-time ratio, 2.5; target international normalized ratios, 2.65 and 9) selected to correspond to the extremes of the accepted therapeutic range in many centers.15 , 16
Rates of thromboembolism were similar in the moderate- and high-intensity groups, but the overall risk of bleeding and the incidence of minor bleeding episodes were significantly greater during high-intensity therapy. The 95 percent confidence intervals for the observed rates of systemic embolism in the two groups remained wide (about 8 to 20 percent), so a moderate but real difference in the efficacy of the two warfarin regimens is still possible, but several considerations led us to terminate the trial at this stage.
First, previously reported rates of thromboembolism are similar to those we observed.1 These rates,4 expressed as episodes per 100 patient-years of follow-up, vary between 1.2 and 9.3 for ball valves, 0.7 and 5.6 for Björk–Shiley valves, and 0.6 and 3.9 for St. Jude valves. Overall, the previously reported incidence is about 4 thromboembolic episodes per 100 patient-years, as compared with 3.85 in our study. Second, it would take a trial of impractical size or duration to seek even the largest difference in rates of systemic embolism between treatment groups that remains consistent with our results (e.g., between 20 and 10 percent, corresponding to event rates of 5.8 and 2.9 per 100 patient-years). Finally, it would be difficult to justify continuing the study in the face of the statistically significant excess of bleeding episodes in the high-intensity group, including two fatal episodes.
Major bleeding has been reported in about 2.4 percent of patients during long-term therapy with oral anticoagulants after valve replacement, and fatal bleeding in 1.7 percent.17 These figures can be compared with those for our patients: major bleeding (none fatal) in 3.3 percent of the patients in our moderate-intensity group and 7.2 percent of those in our high-intensity group (1.6 percent fatal). The consideration of rates of major bleeding per 100 patient-years allows more direct comparisons. The rate was about 1.7 in previous surveys,17 as compared with 0.95 and 2.1 in our moderate- and high-intensity groups, respectively.
This study confirms the presence of a direct relation between the intensity of anticoagulation and the risk of bleeding. Of the 13 major bleeding episodes in our patients, 9 occurred when the prothrombin-time ratio was above 3.0 (international normalized ratio, >10.0); the remaining four, in which the ratio was between 1.6 and 2.1, had recognizable precipitating factors.
There was also a relation between thromboembolism and the prothrombin-time ratio, since 18 of the 33 embolic events (54 percent) were associated with a ratio of 1.3 or less at onset. Factors other than the adequacy of warfarin therapy may have a role at higher levels of anticoagulation, such as the type of valve prosthesis — thromboembolism was most frequent in patients with Beall valves and least frequent in those with St. Jude valves.
Eleven patients were lost to follow-up. All had been seen for at least six months after surgery, and none had had thromboembolic or bleeding episodes.
The study was not double blind, since the investigators who saw the patients during follow-up needed to adjust the warfarin dosage to attain the targeted prothrombin-time ratio. To avoid bias, all the patients were asked a uniform set of questions about thromboembolism and bleeding at every visit to the anticoagulation clinic.
Controlled trials have shown that secondary prevention after venous thromboembolism requires a less intense anticoagulant effect (international normalized ratio, 2.0 to 2.5) than was previously thought.14 More recently, it has become apparent that increasing the target range of the international normalized ratio from between 2.0 and 2.25 to between 2.5 and 4.0 in patients treated with warfarin for three months after the implantation of a tissue heart valve confers no therapeutic benefit, but carries an increased risk of bleeding.18 We now demonstrate that a moderate warfarin effect is also sufficient for the long-term treatment of patients with mechanical heart valves.
We are indebted to W. Greer, Ph.D., chairman of the Department of Biomedical Statistics and Scientific Computing, for his valuable assistance with the statistical analysis.
Source Information
From the Department of Medicine, King Faisal Specialist Hospital and Research Centre (J.N.S., J.O.S.), and King Saud University (L.A.R.M.), Riyadh, Saudi Arabia, and Flinders Medical Centre, Bedford Park, Australia (A.S.G.). Address reprint requests to Dr. Saour at the Department of Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.
- References
References
1
Stein
Web of Science | Medline2
Dale
CrossRef | Web of Science | Medline3
Horstkotte D, Körfer R. The influence of prosthetic valve replacement on the natural history of severe acquired heart lesions: a comparison of complications and clinical and hemodynamic findings after implantation of Björk–Shiley, St. Jude Medical, and other heart valve prostheses. In: De Bakey ME, ed. Advances in cardiac valves: clinical perspectives. New York: Yorke Medical Books, 1983:47–86.
4
Chesebro
CrossRef | Web of Science | Medline5
Christo
CrossRef | Web of Science | Medline6
Yeh 7
Duvoisin 8
Akbarian
Web of Science | Medline9
Friedli
CrossRef | Web of Science | Medline10
Barnhorst
CrossRef | Web of Science | Medline11
Fuster
Web of Science12
Poller
CrossRef | Web of Science | Medline13
Hirsh
Web of Science | Medline14
Hull
Full Text | Web of Science | Medline15
Chesebro
CrossRef | Web of Science | Medline16
Czer
CrossRef | Web of Science | Medline17
Levine
Web of Science | Medline18
Turpie
CrossRef | Web of Science | Medline
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1
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CrossRef2
I. Marie, P. Leprince, J.- F. Menard, C. Tharasse, H. Levesque. (2011) Risk factors of vitamin K antagonist overcoagulation. QJM
CrossRef3
Allison Burnett, Jason Cohen, David A. Garcia. 2011. Hemorrhagic Complications of Anticoagulants in Hospitalized Patients. , 291-330.
CrossRef4
Ramiro Jervis, Andrew Dunn. 2011. Perioperative Management of Oral Anticoagulants and Antiplatelet Agents. , 161-177.
CrossRef5
G. Y. H. Lip, F. Andreotti, L. Fauchier, K. Huber, E. Hylek, E. Knight, D. A. Lane, M. Levi, F. Marin, G. Palareti, P. Kirchhof, , J.-P. Collet, A. Rubboli, D. Poli, J. Camm. (2011) Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace 13:5, 723-746
CrossRef6
M. Levi, E. S. Eerenberg, P. W. Kampuisen. (2011) Anticoagulants. Hämostaseologie 31:4, 229-235
CrossRef7
G. Y. H. Lip, F. Andreotti, L. Fauchier, K. Huber, E. Hylek, E. Knight, D. Lane, M. Levi, F. Marín, G. Palareti, P. Kirchhof. (2011) Bleeding risk assessment and management in atrial fibrillation patients. Thrombosis and Haemostasis 106:6,
CrossRef8
Vasileios K Kouritas, Antonios G Roussakis, Konstantinos Soultanis, Ion Bellenis. (2011) Extrathoracic chronic heamatoma presenting as a chest wall tumor 2 years after a blunt thoracic injury. Journal of Cardiothoracic Surgery 6:1, 156
CrossRef9
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CrossRef10
L. LINKINS, M. O’DONNELL, J. A. JULIAN, C. KEARON. (2010) Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy. Journal of Thrombosis and Haemostasis 8:10, 2201-2207
CrossRef11
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CrossRef12
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CrossRef13
Joan-Carles Trullas-Vila, Josep Bisbe-Company, Adriana Freitas-Ramírez, Silvia Soler-Simon, Vicenta Bisbe-Company, Josep-Maria Roncero-Vidal, Rosa Gispert-Magarolas. (2009) Ten-year experience with acenocoumarol treatment in an ambulatory cohort of Spanish patients. Journal of Thrombosis and Thrombolysis 28:4, 436-443
CrossRef14
Paolo Stassano, Luigi Di Tommaso, Mario Monaco, Francesco Iorio, Paolo Pepino, Nicola Spampinato, Carlo Vosa. (2009) Aortic Valve Replacement. Journal of the American College of Cardiology 54:20, 1862-1868
CrossRef15
Ralph AH Stewart. (2009) Clinical trials in heart valve disease. Current Opinion in Cardiology 24:4, 279-287
CrossRef16
M. LEVI. (2009) Epidemiology and management of bleeding in patients using vitamin K antagonists. Journal of Thrombosis and Haemostasis 7, 103-106
CrossRef17
Gregory J. del Zoppo. 2009. Acute Thrombolysis in Ischemic Cerebrovascular Disease. , 617-650.
CrossRef18
Saket Agarwal, Sanjeev Gupta, Harpreet Singh Minhas, Muhammad Abid Geelani, Shiv Sagar Mandiye, Amit Banerjee. (2009) Comparison of outcomes after mitral valve replacement with a mechanical versus a bioprosthetic valve in patients between forty and sixty years of age. Indian Journal of Thoracic and Cardiovascular Surgery 25:1, 12-17
CrossRef19
Robert O. Bonow, Blase A. Carabello, Kanu Chatterjee, Antonio C. de Leon, David P. Faxon, Michael D. Freed, William H. Gaasch, Bruce W. Lytle, Rick A. Nishimura, Patrick T. O'Gara, Robert A. O'Rourke, Catherine M. Otto, Pravin M. Shah, Jack S. Shanewise, Rick A. Nishimura, Blase A. Carabello, David P. Faxon, Michael D. Freed, Bruce W. Lytle, Patrick T. O'Gara, Robert A. O'Rourke, Pravin M. Shah. (2008) 2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease. Journal of the American College of Cardiology 52:13, e1-e142
CrossRef20
Jess L. Thompson, Thoralf M. Sundt, Maurice E. Sarano, Paula J. Santrach, Hartzell V. Schaff. (2008) In-Patient International Normalized Ratio Self-Testing Instruction After Mechanical Heart Valve Implantation. The Annals of Thoracic Surgery 85:6, 2046-2050
CrossRef21
Antonio Russo, Francesco Grigioni, Jean-François Avierinos, William K. Freeman, Rakesh Suri, Hector Michelena, Robert Brown, Thoralf M. Sundt, Maurice Enriquez-Sarano. (2008) Thromboembolic Complications After Surgical Correction of Mitral Regurgitation. Journal of the American College of Cardiology 51:12, 1203-1211
CrossRef22
R. Ascione, L. Culliford, C.A. Rogers, J. Wild, P. Narajan, G.D. Angelini. (2008) Mechanical Heart Valves in Septuagenarians. Journal of Cardiac Surgery 23:1, 8-16
CrossRef23
Leonid Goubergrits, Ulrich Kertzscher, Klaus Affeld, Christoph Petz, Detlev Stalling, Hans-Christian Hege. (2008) Numerical Dye Washout Method as a Tool for Characterizing the Heart Valve Flow: Study of Three Standard Mechanical Heart Valves. ASAIO Journal 54:1, 50-57
CrossRef24
Roel Vink, Pieter-Willem Kamphuisen, Renée B van den Brink, Marcel Levi. (2007) Challenges in managing anticoagulant therapy in patients with heart valve prostheses. Expert Review of Cardiovascular Therapy 5:3, 563-570
CrossRef25
Leonid Goubergrits. (2006) Numerical modeling of blood damage: current status, challenges and future prospects. Expert Review of Medical Devices 3:5, 527-531
CrossRef26
Robert O. Bonow, Blase A. Carabello, Kanu Chatterjee, Antonio C. de Leon, David P. Faxon, Michael D. Freed, William H. Gaasch, Bruce Whitney Lytle, Rick A. Nishimura, Patrick T. O’Gara, Robert A. O’Rourke, Catherine M. Otto, Pravin M. Shah, Jack S. Shanewise, Sidney C. Smith, Alice K. Jacobs, Cynthia D. Adams, Jeffrey L. Anderson, Elliott M. Antman, David P. Faxon, Valentin Fuster, Jonathan L. Halperin, Loren F. Hiratzka, Sharon A. Hunt, Bruce W. Lytle, Rick Nishimura, Richard L. Page, Barbara Riegel. (2006) ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease. Journal of the American College of Cardiology 48:3, e1-e148
CrossRef27
Alexander Kulik, Fraser D. Rubens, Philip S. Wells, Clive Kearon, Thierry G. Mesana, Judith van Berkom, B.-Khanh Lam. (2006) Early Postoperative Anticoagulation After Mechanical Valve Replacement: A Systematic Review. The Annals of Thoracic Surgery 81:2, 770-781
CrossRef28
2005. Hypertension (High Blood Pressure). .
CrossRef29
2005. Anticoagulants. .
CrossRef30
Detlef Hering, Cornelia Piper, Dieter Horstkotte. (2005) Drug Insight: an overview of current anticoagulation therapy after heart valve replacement. Nature Clinical Practice Cardiovascular Medicine 2:8, 415-422
CrossRef31
2005. Anticoagulants. .
CrossRef32
Constantin Stefanidis, Albert M. Nana, Didier De Cannière, Martine Antoine, Jean-Luc Jansens, Chi-Hoang Huynh, Jean-Louis Le Clerc. (2005) 10-Year Experience With the ATS Mechanical Valve in the Mitral Position. The Annals of Thoracic Surgery 79:6, 1934-1938
CrossRef33
J. H. S. You, F. W. H. Chan, R. S. M. Wong, G. Cheng. (2005) Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation?. British Journal of Clinical Pharmacology 59:5, 582-587
CrossRef34
Alexander J. Sutton, Nicola J. Cooper, Keith R. Abrams, Paul C. Lambert, David R. Jones. (2005) A Bayesian approach to evaluating net clinical benefit allowed for parameter uncertainty. Journal of Clinical Epidemiology 58:1, 26-40
CrossRef35
Roel Vink, Roderik A. Kraaijenhagen, Marcel Levi. (2004) Reply. Journal of the American College of Cardiology 44:5, 1144-1145
CrossRef36
Eric G. Butchart, Christa Gohlke-Bärwolf. (2004) Anticoagulation management of patients with prosthetic valves. Journal of the American College of Cardiology 44:5, 1143-1144
CrossRef37
L. Poller. (2004) International Normalized Ratios (INR): the first 20 years. Journal of Thrombosis and Haemostasis 2:6, 849-860
CrossRef38
Ann K. Wittkowsky, Kelly S. Whitely, Emily Beth Devine, Edith Nutescu. (2004) Effect of Age on International Normalized Ratio at the Time of Major Bleeding in Patients Treated with Warfarin. Pharmacotherapy 24:5, 600-605
CrossRef39
Rachel Koreth, Craig Weinert, Daniel J. Weisdorf, Nigel S. Key. (2004) Measurement of bleeding severity: a critical review. Transfusion 44:4, 605-617
CrossRef40
Oscar Benavente, David Sherman. 2004. Secondary Prevention of Cardioembolic Stroke. , 1171-1186.
CrossRef41
Ratna Magotra. (2004) Prosthetic heart valve replacement—Which one?. Indian Journal of Thoracic and Cardiovascular Surgery 20:S1, 79-80
CrossRef42
(2003) Warfarin Prophylaxis in the Antiphospholipid Antibody Syndrome. New England Journal of Medicine 349:26, 2568-2570
Full Text43
G Hanania, J.P Maroni, Y El Hajj. (2003) L’anticoagulation des prothèses valvulaires. Annales de Cardiologie et d'Angéiologie 52:5, 290-296
CrossRef44
D. Gustafsson. (2003) Oral direct thrombin inhibitors in clinical development. Journal of Internal Medicine 254:4, 322-334
CrossRef45
David Gustafsson, Margareta Elg. (2003) The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review. Thrombosis Research 109, S9-S15
CrossRef46
Jack Hirsh, Valentin Fuster, Jack Ansell, Jonathan L Halperin. (2003) American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Journal of the American College of Cardiology 41:9, 1633-1652
CrossRef47
Daniela Poli, Emilia Antonucci, Alessandra Lombardi, Vieri Boddi, Gian Franco Gensini, Rosanna Abbate, Domenico Prisco. (2003) Low rate of bleeding and thrombotic complications of oral anticoagulant therapy independent of age in the real-practice of an anticoagulation clinic. Blood Coagulation & Fibrinolysis 14:3, 269-275
CrossRef48
Daniela Poli, Emilia Antonucci, Alessandra Lombardi, Vieri Boddi, Gian Gensini, Rosanna Abbate, Domenico Prisco. (2003) Blood Coagulation & Fibrinolysis 14:3, 269-275
CrossRef49
Kelvin H.H Lim, Massimo Caputo, Raimondo Ascione, Jan Wild, Robert West, Gianni D Angelini, Alan J Bryan, Sponsor: Antonio Maria Calafiore. (2002) Prospective randomized comparison of CarboMedics and St Jude Medical bileaflet mechanical heart valve prostheses: An interim report. The Journal of Thoracic and Cardiovascular Surgery 123:1, 21-32
CrossRef50
Donald D. Tresch. (2001) Evaluation and Management of Cardiac Arrhythmias in the Elderly. Medical Clinics of North America 85:2, 527-550
CrossRef51
Amin M. Al-Ahmad, Denise Hartnett-Daudelin, Deeb N. Salem. (2001) Antithrombotic therapy for prosthetic valves: Routine treatment and special considerations. Current Cardiology Reports 3:1, 85-89
CrossRef52
Karl Hammermeister, Gulshan K Sethi, William G Henderson, Frederick L Grover, Charles Oprian, Shahbudin H Rahimtoola. (2000) Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. Journal of the American College of Cardiology 36:4, 1152-1158
CrossRef53
B Kassaï. (2000) Comparison of bioprosthesis and mechanical valves, a meta-analysis of randomised clinical trials. Cardiovascular Surgery 8:6, 477-483
CrossRef54
Tammy J. Bungard, Margaret L. Ackman, Geotham Ho, Ross T. Tsuyuki. (2000) Adequacy of Anticoagulation in Patients with Atrial Fibrillation Coming to a Hospital. Pharmacotherapy 20:9, 1060-1065
CrossRef55
G Rizzoli. (1999) Reoperations for acute prosthetic thrombosis and pannus: an assessment of rates, relationship and risk. European Journal of Cardio-Thoracic Surgery 16:1, 74-80
CrossRef56
W Jamieson. (1999) Bileaflet mechanical prostheses performance in mitral position. European Journal of Cardio-Thoracic Surgery 15:6, 786-794
CrossRef57
Hazzaa Al-Zahrani, Shannon M. Bates, Jeffrey I. Weitz. (1999) Deep vein thrombosis. Current Treatment Options in Cardiovascular Medicine 1:1, 43-53
CrossRef58
RobertO. Bonow, Blase Carabello, AntonioC. de Leon, L.Henry Edmunds, BradleyJ. Fedderly, MichaelD. Freed, WilliamH. Gaasch, CharlesR. McKay, RickA. Nishimura, PatrickT. O’Gara, RobertA. O’Rourke, ShahbudinH. Rahimtoola, JamesL. Ritchie, MelvinD. Cheitlin, KimA. Eagle, TimothyJ. Gardner, Arthur Garson, RaymondJ. Gibbons, RobertA. O’Rourke, RichardO. Russell, ThomasJ. Ryan, SidneyC. Smith. (1998) ACC/AHA guidelines for the management of patients with valvular heart disease. Journal of the American College of Cardiology 32:5, 1486-1582
CrossRef59
A.C. Butler, R.C. Tait. (1998) Management of oral anticoagulant-induced intracranial haemorrhage. Blood Reviews 12:1, 35-44
CrossRef60
J Ninet. (1998) Mechanical versus biological isolated aortic valvular replacement after the age of 70: equivalent long-term results. European Journal of Cardio-Thoracic Surgery 13:1, 84-89
CrossRef61
Vongpatanasin, Wanpen, Hillis, L. David, Lange, Richard A., . (1996) Prosthetic Heart Valves. New England Journal of Medicine 335:6, 407-416
Full Text62
J.Francisco Nistal, Aquilino Hurlé, José M. Revuelta, Marco Gandarillas. (1996) Clinical experience with the carbomedics valve: Early results with a new bileaflet mechanical prosthesis. The Journal of Thoracic and Cardiovascular Surgery 112:1, 59-68
CrossRef63
Aida J. Azar, Suzanne C. Cannegieter, Jaap W. Deckers, Ernest Briët, Paul F.M.M. van Bergen, Jan J.C. Jonker, Frits R. Rosendaal. (1996) Optimal intensity of oral anticoagulant therapy after myocardial infarction. Journal of the American College of Cardiology 27:6, 1349-1355
CrossRef64
Joseph L. Blackshear, John A. Odell. (1996) Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. The Annals of Thoracic Surgery 61:2, 755-759
CrossRef65
Lynn B. McGrath, Javier Fernandez, Glenn W. Laub, William A. Anderson, Bridget M. Bailey, Chao Chen. (1995) Perioperative events in patients with failed mechanical and bioprosthetic valves. The Annals of Thoracic Surgery 60, S475-S478
CrossRef66
Cannegieter, S.C.Rosendaal, F.R.Wintzen, A.R.van der Meer, F.J.M.Vandenbroucke, J.P.Briet, E.. (1995) Optimal Oral Anticoagulant Therapy in Patients with Mechanical Heart Valves. New England Journal of Medicine 333:1, 11-17
Full Text67
Fihn, Stephan D., . (1995) Aiming for Safe Anticoagulation. New England Journal of Medicine 333:1, 54-55
Full Text68
Khamashta, Munther A., Cuadrado, Maria Jose, Mujic, Fedza, Taub, Nick A., Hunt, Beverley J., Hughes, Graham R.V., . (1995) The Management of Thrombosis in the Antiphospholipid-Antibody Syndrome. New England Journal of Medicine 332:15, 993-997
Full Text69
Magda Heras, James H. Chesebro, Valentin Fuster, William J. Penny, Diane E. Grill, Kent R. Bailey, Gordon K. Danielson, Thomas A. Orszulak, James R. Pluth, Francisco J. Puga, Hartzell V. Schaff, Jeffrey J. Larsonkeller. (1995) High risk of thromboemboli early after bioprosthetic cardiac valve replacement. Journal of the American College of Cardiology 25:5, 1111-1119
CrossRef70
(1994) Warfarin and Aspirin after Heart-Valve Replacement. New England Journal of Medicine 330:7, 507-509
Full Text71
Richard Sinert, Thomas Scalea. (1994) Retropharyngeal and Bowel Hematomas in an Anticoagulated Patient. Academic Emergency Medicine 1:1, 67-72
CrossRef72
J. Saour, A. Gallus. (1993) Warfarin: is it time to reduce target ranges again?. Australian and New Zealand Journal of Medicine 23:6, 692-696
CrossRef73
Eckman, Mark H.Levine, Herbert J.Pauker, Stephen G.. (1993) Effect of Laboratory Variation in the Prothrombin-Time Ratio on the Results of Oral Anticoagulant Therapy. New England Journal of Medicine 329:10, 696-702
Full Text74
Turpie, AlexanderGent, MichaelLaupacis, AndreasLatour, YvesGunstensen, JohnBasile, FadiKlimek, MarianHirsh, Jack. (1993) A Comparison of Aspirin with Placebo in Patients Treated with Warfarin after Heart-Valve Replacement. New England Journal of Medicine 329:8, 524-529
Full Text75
Hammermeister, Karl E.Sethi, Gulshan K.Henderson, William G.Oprian, CharlesKim, TaiRahimtoola, Shahbudin. (1993) A Comparison of Outcomes in Men 11 Years after Heart-Valve Replacement with a Mechanical Valve or Bioprosthesis. New England Journal of Medicine 328:18, 1289-1296
Full Text76
W.R. Eric Jamieson. (1993) Modern Cardiac Valve Devices? Bioprostheses and Mechanical Prostheses: State of the Art. Journal of Cardiac Surgery 8:1, 89-98
CrossRef77
G.Patrick Clagett. (1992) Antithrombotic therapy for lower extremity bypass. Journal of Vascular Surgery 15:5, 873-875
CrossRef78
L. Poller. (1992) Therapeutic ranges for oral anticoagulation in different thromboembolic disorders. Annals of Hematology 64:2, 52-59
CrossRef79
(1992) Oral Anticoagulant Drugs. New England Journal of Medicine 326:1, 68-69
Full Text80
J. W. J. van Wersch, C. H. van Mourik-Alderliesten, A. Coremans. (1992) Comparison of Markers of Coagulation Activation in Patients Under Oral Anticoagulation at Different Levels. Clinical Chemistry and Laboratory Medicine 30:8, 461-466
CrossRef81
(1991) The Effect of Low-Dose Warfarin on the Risk of Stroke in Patients with Nonrheumatic Atrial Fibrillation. New England Journal of Medicine 325:2, 129-132
Full Text82
Oates, John A., Wood, Alastair J.J., , Hirsh, Jack, . (1991) Oral Anticoagulant Drugs. New England Journal of Medicine 324:26, 1865-1875
Full Text83
Daphne T. Hsu, Linda J. Addonizio, Allan J. Hordof, Welton M. Gersony. (1991) Acute pulmonary embolism in pediatric patients awaiting heart transplantation. Journal of the American College of Cardiology 17:7, 1621-1625
CrossRef84
G.Patrick Clagett. (1991) Clinical trials: current status and recommendations. Journal of Vascular Surgery 13:5, 761-763
CrossRef85
T. Treasure. (1990) Which heart valves should we use?. The Lancet 336:8723, 1115-1117
CrossRef86
(1990) Anticoagulation and Prosthetic Heart Valves. New England Journal of Medicine 323:11, 756-757
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