Langenbecks Arch Surg (2014) 399:99–107 DOI 10.1007/s00423-013-1149-3
ORIGINAL ARTICLE
Spontaneous and non-spontaneous bleeding complications in patients with oral vitamin K antagonist therapy Martin Hoffmann & Markus Zimmermann & Rüdiger Meyer & Tilman Laubert & Nehara Begum & Tobias Keck & Peter Kujath & Erik Schloericke
Received: 27 April 2013 / Accepted: 25 November 2013 / Published online: 5 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose The aim of the study was to evaluate potential differences between patients with spontaneous and nonspontaneous bleeding episodes during treatment with vitamin K antagonists which mainly resulted in compartment syndromes. Methods The population in this study comprised 116 patients who suffered at least one bleeding complication which required surgical treatment during therapy with an oral vitamin K antagonist. The patients were treated between September 2001 and July 2008. Results Significant differences were observed between the two patient groups with regard to the presence of renal failure, arterial hypertension, and diabetes mellitus, which occurred more frequently in patients with spontaneous bleeding. Also, significantly more patients with spontaneous bleedings developed compartment syndrome that needed emergency operation. Overall mortality was 9.6 %, was associated with multiorgan failure in all patients, and was not different between the two patient groups. Conclusions The identification of high-risk patients before treatment with an oral vitamin K antagonist is of major importance. The existence of over-anticoagulation syndrome and compartment syndrome is associated with significant mortality and morbidity and should not be underestimated. Keywords Compartment syndrome . Over-anticoagulation . Vitamin K antagonist . Surgical management
M. Hoffmann (*) : M. Zimmermann : R. Meyer : T. Laubert : N. Begum : T. Keck : P. Kujath : E. Schloericke Clinic for Surgery, University Clinic of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany e-mail: [email protected]
Introduction Phenprocoumon is a vitamin K antagonist and is used in the prevention of arterial and venous thromboembolism. Apart from this desired effect, the substance also carries an increased risk of potentially life-threatening adverse events as a result of its narrow therapeutic index, high plasma protein binding, and cytochrome P450-dependent metabolism [1, 2]. The most frequent adverse events during treatment with phenprocoumon are bleeding complications. Previous studies have demonstrated a distinctly significant correlation between the elevated risk of bleeding and the international normalized ratio (INR) level, concomitant disorders and genetic polymorphisms, and comedication with drugs that exert an influence on coagulation and the duration of therapy with phenprocoumon. In this context, various threshold values for a markedly elevated risk of bleeding have been described in international literature [3, 4]. Recently published guidelines on the basis of meta-analyses showed that both the initial target INR and an INR of >4.0 at the point in time of the bleeding episode were the most important factors of the manifestation of a bleeding complication [5, 6]. This study was performed in 116 consecutive patients who were treated in the Clinic for Surgery at the University Clinic of Schleswig-Holstein, Campus Luebeck, between September 2001 and July 2007. Intracranial bleeding was not included in this study because this entity is not treated in our department. The aim of this study was to identify the risk factors of the occurrence of bleeding complications requiring surgery in an unselected patient population in a maximum care hospital. Spontaneous and non-spontaneous bleeding episodes were analyzed separately. The importance of a therapeutic algorithm for the initiation of surgical therapy will be discussed.
100
Langenbecks Arch Surg (2014) 399:99–107
Methods The patient population in this study comprised 116 patients who were treated in the Clinic for Surgery of the University Clinic of Schleswig-Holstein, Campus Luebeck, for at least one bleeding complication that required surgical treatment during therapy with the oral vitamin K antagonist phenprocoumon. The patients were prospectively enlisted in our database between September 2001 and July 2008 after informed consent had been obtained. The local ethics committee granted permission for the conduct of the study. The data was analyzed retrospectively. When the database was being compiled, the patient files were checked for the following parameters: 1. 2. 3. 4. 5.
6. 7. 8. 9. 10. 11. 12. 13. 14.
Compartment syndrome Target INR value Patient characteristics Age and sex Indication for treatment with phenprocoumon (atrial fibrillation, implantation of an artificial heart valve, deep vein thrombosis, and pulmonary embolism in the patient's history) History of treatment with phenprocoumon Prior changes in dosing Concomitant disorders that affect bleeding tendency (e.g., renal failure) INR value at the time of bleeding Localization of bleeding Length of inpatient stay, length of ICU stay, and outcome Co-medication with effect on hemostasis Duration of anticoagulation before the onset of overanticoagulation syndrome Type of operation
In addition, the patients were subdivided into groups with spontaneous and non-spontaneous bleeding episodes. Spontaneous bleeding was defined as bleeding into any compartment of the human body without any preexisting episode of any trauma. Non-spontaneous bleeding episodes were defined as bleeding due to any kind of trauma. Table 1 provides an overview of the patient population. Identification of patients All patients were admitted as emergency cases via the emergency room of the University Clinic of Schleswig-Holstein, Campus Luebeck. The study included all patients with a bleeding complication after phenprocoumon intake, which required operative treatment. The patients also had to be at least 18 years of age. Statistical analysis of the data was done with the program SPSS version 16.0.2 implementing the chi-square test. A p
value of0.05). General patient characteristics are shown in Table 1. No statistically significant differences were found in terms of age and sex of the patients. Likewise, there were no differences between the groups with regard to the indication for vitamin K antagonist therapy. In 12 patients, the dose was increased 6 weeks prior to the bleeding event. The INR values observed on admission did not differ significantly from those of the rest of the patient population. Moreover, the preceding INR values before and after dose adjustment were not different from those of the other patients. A large number of co-morbidities were included in the database and statistically analyzed, including—for example—coronary heart disease, arterial hypertension, diabetes mellitus, and the history of cerebral ischemia. Statistical significance was achieved only in the following parameters: serum creatinine, arterial hypertension, and diabetes mellitus (insulin and non-insulin dependent). An increase in serum creatinine to values above 1.51 mg/dL attained statistical significance in the comparison of patients with spontaneous and those with non-spontaneous bleeding. In the group of patients with spontaneous bleeding, these elevated values were demonstrated in 34 cases (46.6 %). Among patients with non-spontaneous bleeding, elevated serum creatinine was observed in only eight patients (18.6 %). This difference was highly statistically significant (p =0.002). A highly significant difference (p
ORIGINAL ARTICLE
Spontaneous and non-spontaneous bleeding complications in patients with oral vitamin K antagonist therapy Martin Hoffmann & Markus Zimmermann & Rüdiger Meyer & Tilman Laubert & Nehara Begum & Tobias Keck & Peter Kujath & Erik Schloericke
Received: 27 April 2013 / Accepted: 25 November 2013 / Published online: 5 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose The aim of the study was to evaluate potential differences between patients with spontaneous and nonspontaneous bleeding episodes during treatment with vitamin K antagonists which mainly resulted in compartment syndromes. Methods The population in this study comprised 116 patients who suffered at least one bleeding complication which required surgical treatment during therapy with an oral vitamin K antagonist. The patients were treated between September 2001 and July 2008. Results Significant differences were observed between the two patient groups with regard to the presence of renal failure, arterial hypertension, and diabetes mellitus, which occurred more frequently in patients with spontaneous bleeding. Also, significantly more patients with spontaneous bleedings developed compartment syndrome that needed emergency operation. Overall mortality was 9.6 %, was associated with multiorgan failure in all patients, and was not different between the two patient groups. Conclusions The identification of high-risk patients before treatment with an oral vitamin K antagonist is of major importance. The existence of over-anticoagulation syndrome and compartment syndrome is associated with significant mortality and morbidity and should not be underestimated. Keywords Compartment syndrome . Over-anticoagulation . Vitamin K antagonist . Surgical management
M. Hoffmann (*) : M. Zimmermann : R. Meyer : T. Laubert : N. Begum : T. Keck : P. Kujath : E. Schloericke Clinic for Surgery, University Clinic of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany e-mail: [email protected]
Introduction Phenprocoumon is a vitamin K antagonist and is used in the prevention of arterial and venous thromboembolism. Apart from this desired effect, the substance also carries an increased risk of potentially life-threatening adverse events as a result of its narrow therapeutic index, high plasma protein binding, and cytochrome P450-dependent metabolism [1, 2]. The most frequent adverse events during treatment with phenprocoumon are bleeding complications. Previous studies have demonstrated a distinctly significant correlation between the elevated risk of bleeding and the international normalized ratio (INR) level, concomitant disorders and genetic polymorphisms, and comedication with drugs that exert an influence on coagulation and the duration of therapy with phenprocoumon. In this context, various threshold values for a markedly elevated risk of bleeding have been described in international literature [3, 4]. Recently published guidelines on the basis of meta-analyses showed that both the initial target INR and an INR of >4.0 at the point in time of the bleeding episode were the most important factors of the manifestation of a bleeding complication [5, 6]. This study was performed in 116 consecutive patients who were treated in the Clinic for Surgery at the University Clinic of Schleswig-Holstein, Campus Luebeck, between September 2001 and July 2007. Intracranial bleeding was not included in this study because this entity is not treated in our department. The aim of this study was to identify the risk factors of the occurrence of bleeding complications requiring surgery in an unselected patient population in a maximum care hospital. Spontaneous and non-spontaneous bleeding episodes were analyzed separately. The importance of a therapeutic algorithm for the initiation of surgical therapy will be discussed.
100
Langenbecks Arch Surg (2014) 399:99–107
Methods The patient population in this study comprised 116 patients who were treated in the Clinic for Surgery of the University Clinic of Schleswig-Holstein, Campus Luebeck, for at least one bleeding complication that required surgical treatment during therapy with the oral vitamin K antagonist phenprocoumon. The patients were prospectively enlisted in our database between September 2001 and July 2008 after informed consent had been obtained. The local ethics committee granted permission for the conduct of the study. The data was analyzed retrospectively. When the database was being compiled, the patient files were checked for the following parameters: 1. 2. 3. 4. 5.
6. 7. 8. 9. 10. 11. 12. 13. 14.
Compartment syndrome Target INR value Patient characteristics Age and sex Indication for treatment with phenprocoumon (atrial fibrillation, implantation of an artificial heart valve, deep vein thrombosis, and pulmonary embolism in the patient's history) History of treatment with phenprocoumon Prior changes in dosing Concomitant disorders that affect bleeding tendency (e.g., renal failure) INR value at the time of bleeding Localization of bleeding Length of inpatient stay, length of ICU stay, and outcome Co-medication with effect on hemostasis Duration of anticoagulation before the onset of overanticoagulation syndrome Type of operation
In addition, the patients were subdivided into groups with spontaneous and non-spontaneous bleeding episodes. Spontaneous bleeding was defined as bleeding into any compartment of the human body without any preexisting episode of any trauma. Non-spontaneous bleeding episodes were defined as bleeding due to any kind of trauma. Table 1 provides an overview of the patient population. Identification of patients All patients were admitted as emergency cases via the emergency room of the University Clinic of Schleswig-Holstein, Campus Luebeck. The study included all patients with a bleeding complication after phenprocoumon intake, which required operative treatment. The patients also had to be at least 18 years of age. Statistical analysis of the data was done with the program SPSS version 16.0.2 implementing the chi-square test. A p
value of0.05). General patient characteristics are shown in Table 1. No statistically significant differences were found in terms of age and sex of the patients. Likewise, there were no differences between the groups with regard to the indication for vitamin K antagonist therapy. In 12 patients, the dose was increased 6 weeks prior to the bleeding event. The INR values observed on admission did not differ significantly from those of the rest of the patient population. Moreover, the preceding INR values before and after dose adjustment were not different from those of the other patients. A large number of co-morbidities were included in the database and statistically analyzed, including—for example—coronary heart disease, arterial hypertension, diabetes mellitus, and the history of cerebral ischemia. Statistical significance was achieved only in the following parameters: serum creatinine, arterial hypertension, and diabetes mellitus (insulin and non-insulin dependent). An increase in serum creatinine to values above 1.51 mg/dL attained statistical significance in the comparison of patients with spontaneous and those with non-spontaneous bleeding. In the group of patients with spontaneous bleeding, these elevated values were demonstrated in 34 cases (46.6 %). Among patients with non-spontaneous bleeding, elevated serum creatinine was observed in only eight patients (18.6 %). This difference was highly statistically significant (p =0.002). A highly significant difference (p
