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(Chest. 2005;127:53-59.)
© 2005 American College of Chest Physicians

Thromboembolic and Bleeding Complications Following St. Jude Medical Valve Replacement*

Results of the German Experience With Low-Intensity Anticoagulation Study

Detlef Hering, MD; Cornelia Piper, MD; Rito Bergemann, MD; Carina Hillenbach, PhD; Manfred Dahm, MD; Christof Huth, MD and Dieter Horstkotte, MD

* From the Department of Cardiology (Drs. Hering, Piper, and Horstkotte), Heart Center North-Rhine Westphalia, Bad Oeynhausen; Institute for Medical Outcome Research (Drs. Bergemann and Hillenbach), Loerrach; Department of Cardiothoracic and Vascular Surgery (Dr. Dahm), University Hospital Mainz, Mainz; and Department of Cardiothoracic Surgery (Dr. Huth), Otto-von-Guericke-University, Magdeburg, Germany.

Correspondence to: Dieter Horstkotte, MD, Department of Cardiology, Heart Center North-Rhine Westphalia, Ruhr University, Bad Oeynhausen, Georgstrasse 11, 32545 Bad Oeynhausen, Germany; e-mail: akohlstaedt{at}hdz-nrw.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Due to their inherent thrombogenicity, mechanical cardiac valves necessitate lifelong oral anticoagulation. Less intensive oral anticoagulation than recommended earlier might result in a lower incidence of bleeding complications without increasing the embolic hazard significantly.

Design: Comparison of three different intensities of oral anticoagulation in a prospective, randomized multicenter design. Three months after valve replacement, patients were randomly assigned to stratum A, international normalized ratio (INR) 3.0 to 4.5; stratum B, INR 2.5 to 4.0; or stratum C, INR 2.0 to 3.5.

Patients: Data from 2,735 patients following aortic valve replacement (AVR; n = 2,024), mitral valve replacement (MVR; n = 553), and combined AVR and MVR (n = 158) with the St. Jude Medical (SJM) valve (St. Jude Medical; St. Paul, MN) between July 1993 and May 1999 were analyzed, covering a total follow-up period of 6,801 patient-years. All complications were registered prospectively.

Measurements and results: Fifty-one thromboembolic events (TEs) were documented, resulting in a linearized incidence of 0.75 TEs per 100 patient-years, 22 of which were minor (0.32% per patient-year), 10 were moderate (0.15% per patient-year), and 19 were severe (0.28% per patient-year). Thromboembolism following AVR was significantly lower than after MVR (0.53% per patient-year vs 1.64% per patient-year). Patients reported 1,687 bleeding complications (24.8% per patient-year). The vast majority of bleeding complications (n = 1,509; 22.2% per patient-year) were classified as minor, 140 were classified as moderate (2.06% per patient-year), and 38 were classified as severe (0.56% per patient-year). The clinically relevant incidences of moderate and severe TEs and bleeding complications were not significantly different between the three prespecified INR strata.

Conclusions: The intention-to-treat analysis of the results of the German Experience With Low Intensity Anticoagulation study leads to the unexpected result that despite a sophisticated reporting system, the incidence of moderate and severe TE and bleeding complications was comparably low in all INR strata and more or less within the so-called background incidence reported for an age-related "normal" population. This study supports reexamination of the intensity of anticoagulation in patients with the SJM valve.

Key Words: anticoagulation • bleeding complication • German Experience With Low Intensity Anticoagulation • international normalized ratio • prosthetic cardiac valve • St. Jude Medical valve • thromboembolic complication


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Due to their inherent thrombogenicity, mechanical cardiac valves necessitate lifelong oral anticoagulation.1234 More effective prevention of thromboembolic events (TEs) expected by a more intensive anticoagulation has to be weighed against an increase in bleeding complications. The optimal intensity of oral anticoagulation is characterized by the lowest rate of both TEs and bleeding complications.5 Whereas numerous follow-up series report TE incidences after valve replacement surgery, prospective randomized trials comparing different intensities of oral anticoagulation are scarce.

The thromboembolic hazard is not only related to the type of prosthesis implanted, but to a variety of concomitant patient-related risk factors.56 Current guidelines234 differ with respect to the recommended target levels of oral anticoagulation and the modification of anticoagulation therapy in special situations (eg, noncardiac surgery or pregnancy). For over a decade, it has been reported that less intensive oral anticoagulation than previously recommended results in a lower incidence of bleeding complications without a significant increase of TEs.7891011 These findings prompted the German Experience With Low Intensity Anticoagulation (GELIA) study,12 which compared three different intensities of oral anticoagulation in a prospective, randomized multicenter design. This article reports the results of the GELIA study on the basis of a comprehensive intention-to-treat analysis, and intends to make the GELIA data comparable to the material already existing in the scientific literature.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The design of the GELIA study has been described in detail elsewhere.12 Briefly, patients were randomly assigned to three intensities of oral anticoagulation: stratum A, international normalized ratio (INR) 3.0 to 4.5; stratum B, INR 2.5 to 4.0; and stratum C, INR 2.0 to 3.5. Patients were eligible for study inclusion if they had aortic valve replacement (AVR), mitral valve replacement (MVR), or combined aortic and mitral valve replacement with a St. Jude Medical (SJM) cardiac valve (St. Jude Medical; St. Paul, MN) prosthesis in the 29 participating centers. Patients with previous or concomitant coronary bypass surgery, reconstructive surgery of another cardiac valve, emergency operation, or valve replacement for infective endocarditis were included. Main exclusion criteria were contraindications for treatment with coumarin, history or current evidence of coagulation abnormalities not allowing for assignment to a random treatment stratum, preexisting anticoagulant therapy with a given intensity for indications unrelated to valve replacement, and/or a valve other than a SJM prosthetic cardiac valve implanted.

Because of the increased TE risk early after surgery (inconstant hazard), randomization to the three INR strata was started only 3 months postoperatively. Special emphasis was placed on complete recording of all complications occurring during follow-up. Patients therefore received documentation cards covering a 3-month period in order to register complications prospectively (on-site documentation). New documentation cards were provided by the administrative monitoring center 2 weeks before the end of each of the 3-month periods. Patients’ reports were cross-checked by contacting the treating physicians if more than minor complications had been recorded or if their documentation cards were filled out in an equivocal way. TE and bleeding complications were analyzed separately. Cases in which it was impossible to determine whether clinical signs or symptoms were caused by TE or bleeding complications were collected in a third group of complications, termed thromboembolism or bleeding complications.

Complications were classified according to a modified Karnofsky scale, which had been described in detail and used previously7812131415 and proven to be more precise than reporting systems for morbid events recommended by the American Association of Thoracic Surgeons and the Society of Thoracic Surgeons (AATS/STS).16 A recent comparison of the adapted Karnofsky criteria and the AATS/STS guidelines revealed that bleeding rates were reported more and thromboembolic rates less frequent when utilizing the Karnofsky reporting system.17

The study protocol of the GELIA study complied with the principles of the Helsinki Declaration and was approved by the ethical committee of the principal study center. All patients were informed thoroughly about the objectives of the study and gave their informed consent for participation.

Patient recruitment was stopped according to the protocol after 2,848 patients had been enrolled between July 1993 and May 1999. The final hypothesis was tested as planned after another 13 months of follow-up.

After exclusion of 11 patients not available during follow-up and 102 patients who died within 90 days of surgery (90-day mortality rate of 3.6%) and thus before the study-specific follow-up was started, 2,735 patients were available for final analysis covering a total follow-up period of 6,801 patient-years. Of these, 2,024 patients had AVR, 553 had MVR, and 158 had AVR plus MVR. Demographic characteristics of the patient population and clinical data concerning additional thromboembolic risk factors are given in Tables 1, 2 .


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  		Table 1. Patient Characteristics*

 

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  		Table 2. Quality of Anticoagulation in the GELIA Study Cohort

 
Statistical Analysis
Data management and statistical analysis were performed by the Institute for Medical Outcome Research, Loerrach, Germany. Complication rates are reported as linearized incidences per 100 patient-years; 95% confidence intervals (CIs) were calculated according to Pearson-Clopper.18 For this article, clinical data were analyzed according to the intention-to-treat principle, which is based on the projected ("erratic"), not the actually achieved INR levels. The combined primary end point of the study was the number of serious (grade II or grade III) TE and bleeding complications for each stratum of anticoagulation intensity. The {chi}2 without continuity correction was used for detection of statistically significant differences among the three target INR intensities (strata). Results are given separately for patients after AVR, MVR, and AVR plus MVR.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The percentage of concomitant thromboembolic risk factors was lowest in patients with AVR. The percentage of patients with sinus rhythm at discharge was almost two times higher than in patients after MVR or AVR plus MVR.

Oral anticoagulation management in this closely followed study population was of high quality; 90.2% of a total of 121,987 INR measurements were inside the therapeutic corridor. Details are given in Table 2. Interestingly, the percentage of INR measurements inside the randomly assigned target ranges (strata A, B, and C) differed significantly from 44.5% (stratum A), 62.2% (stratum B), to 74.5% (stratum C).

A total of 51 TEs were documented for the entire study population, resulting in a linearized incidence of 0.75 TEs per 100 patient-years. Twenty-two TEs were due to minor events (grade I; 0.32% per patient-year), 10 were due to moderate events (grade II; 0.15% per patient-year), and 19 were due to severe events (grade III; 0.28% per patient-year) events. After AVR, the total TE incidence was 0.53% per patient-year, which was significantly lower than for MVR (1.64% per patient-year; p = 0.0002) [Table 3 ]. Patients after AVR plus MVR reported a total TE incidence of 0.79% per patient-year, which neither differed from patients with isolated AVR nor from patients with isolated MVR. In comparison, patients after MVR experienced a higher number of both minor (grade I; p = 0.001) and severe (grade III; p < 0.02) TES. No prosthetic valve thrombosis was observed.


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  		Table 3. Total Number of TEs and TE Incidence per 100 Patient-Years Following SJM Valve Replacement in AVR, MVR, or AVR Plus MVR Positions*

 
Patients reported 1,687 bleeding complications during the follow-up, a linearized incidence of 24.8 bleedings per patient-year. However, the vast majority of these complications were minor (grade I) bleeding (n = 1,509; 22.2% per patient-year), 140 bleedings were moderate (grade II; 2.06% per patient-year), and 38 were severe (grade III; 0.56% per patient-year) [Table 4 ]. Total bleeding incidence was 21.8% per patient-year after AVR, 32.3% per patient-year after MVR (p < 0.0001 vs AVR), and 40.7% per patient-year after AVR plus MVR (p < 0.0001 vs AVR; p < 0.02 vs MVR). Differences in overall bleeding complications between the patient subgroups were entirely due to minor bleedings, whereas the incidence of clinically relevant moderate or severe (grade II and III) bleedings was not significantly different among groups.


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  		Table 4. Total Number of Bleeding Complications and Bleeding Incidence per 100 Patient-Years Following SJM Valve Replacement in AVR, MVR, or AVR Plus MVR Positions

 
For 10 complications, mostly cerebral events where no cranial CT scans were available, it remained unclear whether they had been caused by TEs or bleeding complications. These complications (linearized incidence, 0.18; 95% CI, 0 to 0.4 after AVR; linearized incidence, 0.10, 95% CI, 0 to 0.4 after MVR) were grouped separately.

The linearized incidences of complications after AVR and MVR according to the intended INR strata are listed in Tables 5, 6 . The number of events in the AVR plus MVR group was too small to draw meaningful conclusions. With one exception (a higher number of minor thromboembolic complications in patients with mitral valve prostheses randomized to stratum C in comparison to stratum B), TE incidences were not different among the three INR strata. Significant differences regarding minor bleeding complications were observed among the three INR strata. Only for the largest patient subgroup following AVR, an expected gradual decrease of minor bleeding complications from INR stratum A to C was demonstrated. Of note, the incidence of clinically important moderate and severe bleeding complications was not significantly different among the three prespecified INR strata, irrespective of the site of prosthetic valve implantation.


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  		Table 5. TE After SJM Valve Replacement Differentiated by the Intended INR Stratum Following AVR and MVR*

 

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  		Table 6. Bleeding Complications After SJM Valve Replacement Differentiated by the Intended INR Stratum Following AVR and MVR*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Oral anticoagulation using coumarin is the treatment of choice to prevent thromboembolic complications after implantation of mechanical heart valve prostheses, yet without a real alternative.1234 Withholding anticoagulation or using platelet function inhibitors alone yield unsatisfactory or even disastrous results.1719202122 When the GELIA study was designed, practice guidelines generally recommended target INR ranges of 3.0 to 4.5 or even 3.5 to 5.0 for patients with mechanical heart valve prostheses.23242526 These recommendations were supported with low evidence by mostly retrospective studies24 on complication rates following first or second-generation mechanical heart valve prostheses. Prospective randomized studies comparing different intensities of oral anticoagulation were not available.

Prostheses with "improved" designs introduced in the late 1970s appeared to be less thrombogenetic, and lower intensity oral anticoagulation than generally recommended was obviously not associated with an increased thromboembolic hazard.7891011 These observations, however, were also not based on high-quality or even prospective, randomized trials.

The GELIA study was initiated to establish the optimal target for oral anticoagulation in a well-controlled, well-designed, prospective, and randomized comparison utilizing three different intensities of anticoagulation.12 INRs instead of prothrombin times or "quick" levels were used throughout the study. To eliminate the confounding effect of different prosthetic devices, only patients with the SJM bileaflet prosthesis were enrolled.

In a recent review27 of long-term follow-up studies with the SJM prosthesis, average TE rates of 1.58% per patient-year (range, 0.6 to 3.7) after AVR and 2.45% per patient-year (range, 0.3 to 5.1) after MVR were reported. Bleeding complications were observed in 1.32% per patient-year (range, 0.1 to 4.1) and 1.26% per patient-year (range, 0.2 to 2.8), respectively.27 The GELIA results are not directly comparable with these figures because of the meticulous follow-up technique and use of a modified Karnofsky index to grade the severity of complications.7812131415 The high incidence of minor bleeding complications (grade I; eg, small hematomas or bleeding from the gums) in our study is thus the result of a more sophisticated reporting system than that recommended by the AATS/STS,161728 which offers realistic information about the true frequency of TEs and bleeding complications in a sizeable population representing a typical cross-section of heart valve recipients.

It is obvious from our data that a considerable proportion of minor and even major clinical events is missed if patients are followed up retrospectively using questionnaires or if outpatient follow-up intervals are extended to > 6 months.529 In some of the studies28 utilizing inappropriate follow-up techniques, not even the background incidence of hemorrhages and cerebral ischemic attacks (ie, the incidence found in an unselected age-related, so-called "normal" population) has been reported.

The descriptive data analysis presented in this article represents an intention-to-treat analysis. Nearly all published results on bleeding and thromboembolic complication rates after valve replacement surgery are based on intention-to-treat analysis not taking erratic INR values into account.30 This intention-to-treat analysis of the GELIA database failed to demonstrate differences in moderate and severe complication rates among the three strata of different intensities of oral anticoagulation. As > 90% of INR measurements during the entire follow-up period were within the therapeutic range of INR 2.0 to 4.5, which is the lowest erratic INR ever published, we conclude that low-intensity anticoagulation with a target INR of 2.0 to 3.5 is safe for patients with SJM prostheses in the aortic position as well as the mitral position. However, no differences with regard to bleeding or thromboembolic complications were found for patients intended to be treated with higher INR ranges. In contrast to our findings, intention-to-treat analysis of two randomized trials3132 demonstrated a decrease in bleeding complications without an increase in embolic events with so-called low-dose rather than standard-dose oral anticoagulation. In the AREVA study, 380 patients (81% with SJM prostheses and 96% having isolated aortic valve prostheses) were randomized to INR levels of 2.0 to 3.0 vs 3.0 to 4.5.31 While the incidence of TE was comparable between the two groups, significantly less bleeding complications were documented in the group with less intensive oral anticoagulation. However, the incidence of major bleeding complications did not differ between the two groups. Meschengieser and associates32 compared a combination of low-intensity (INR 2.5 to 3.5) oral anticoagulation plus aspirin 100 mg/d with high-intensity oral anticoagulation alone (INR 3.5 to 4.5). The number of embolic events was comparable between the two groups, and major bleeding episodes were insignificantly reduced from 2.33 to 1.13% per patient-year favoring patients with low-intensity anticoagulation. Because aspirin was added in only 1 of the groups, it remains unclear to which extent the results are really due to differences in oral anticoagulation intensities.

On the basis of the studies published so far, contemporary practice guidelines have adopted the concept of low-intensity oral anticoagulation and uniformly recommend an upper INR target of 3.5 for patients carrying a SJM prosthesis. For patients with SJM AVR and no concomitant risk factors, an INR between 2.0 and 3.0 appears to be appropriate.234

In summary, the analysis of the GELIA data on an intention-to-treat basis leads to the unexpected result that three distinct levels of oral anticoagulation ranging from 2.0 to 3.5, 2.5 to 4.0, and 3.0 to 4.5 are essentially equivalent in terms of moderate-to-severe TE and bleeding complications. Despite the sophisticated reporting system, the incidence of moderate and severe TE as well as bleeding complications in all three groups was low and more or less within the so-called background incidence reported for an age-related "normal" population.33 This large-scale, multicenter, randomized, prospective study with a representative patient sample supports a policy of low-intensity anticoagulation in patients with the SJM valve.


   Footnotes
 
Abbreviations: AATS/STS = American Association of Thoracic Surgeons and the Society of Thoracic Surgeons; AVR = aortic valve replacement; CI = confidence interval; GELIA = German Experience With Low Intensity Anticoagulation; INR = international normalized ratio; MVR = mitral valve replacement; SJM = St. Jude Medical; TE = thromboembolic event

GELIA has been made possible by an unrestricted scientific grant from St. Jude Medical Inc., St. Paul, MN.

Received for publication February 19, 2004. Accepted for publication August 11, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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