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WHAT CAN WE LEARN FROM THE THREE MEGATRIALS USING ANTICOAGULANTS IN SEVERE SEPSIS?

2004; Lippincott Williams & Wilkins; Volume: 22; Issue: 6 Linguagem: Inglês

10.1097/01.shk.0000145934.24344.64

1540-0514

Toshiaki Iba, Akio Kidokoro,

Venous Thromboembolism Diagnosis and Management

INTRODUCTION Microthrombus formation and the generation of inflammatory mediators such as thrombin and factor Xa by the activated coagulation system, resulting in disturbance of the microcirculation, are important factors involved in the pathogenesis of organ dysfunction in sepsis (1). Based on this theory, the efficacy of treatment with naturally occurring anticoagulants for severe sepsis has been examined in clinical trials. Recombinant human activated protein C (rhAPC) has become the first drug approved by the Food and Drug Administration (FDA) for the treatment of severe sepsis in the United States. Following the online announcement of success of the rhAPC trial in 2001 in the New England Journal of Medicine (PROWESS trial) (2), the results of two other trials using natural anticoagulants were published: The KyberSept trial [high-dose antithrombin (AT) in patients with severe sepsis] (3) and the OPTIMIST trial [recombinant tissue factor pathway inhibitor (rTFPI) in patients with severe sepsis] (4). Although AT and recombinant TFPI did not show a survival benefit in patients with sepsis, rhAPC did. However, does absence of proof of efficacy provide proof of the absence of efficacy? (5, 6). Because each of these trials enrolled nearly 2000 subjects (OPTIMIST trial) or more (KyberSept trial), we should learn more about sepsis trials and consider the possible causes for the negative findings (7-9). DIFFERENCES OF THE THREE NATURAL ANTICOAGULANTS Differences of their mechanism of action Differences of anti-inflammatory effects Although the mechanisms of function are different, all three agents are naturally occurring anticoagulants. In addition, they also have direct effects on vascular endothelial cells (EC), which are known as “anti-inflammatory effects” (Table 1). AT and rTFPI interact with EC through binding to glycosaminoglycan (GAG) on the endothelial surface (10, 11), whereas APC acts through its specific binding site, endothelial protein C receptor (EPCR), in the presence of thrombomodulin and protein S (12). Recently, it has become evident that the APC/EPCR complex translocates to the nucleus and expresses multiple effects in EC and WBC, including limitation of nuclear factor-κB-mediated proinflammatory activity, attenuation of inflammatory cytokine and chemokine generation, and up-regulation of antiapoptotic genes (13). Similarly, AT revealed to have anti-inflammatory effects on EC, which include the up-regulation of PGI2 production and suppression in proinflammatory cytokine production and leukocyte-endothelial interaction (14). In case of TFPI, the details of the protective effects have not been fully elucidated; however, it was reported that TFPI reduced the mortality in the primate model of sepsis through the regulation of cytokines and cellular protection (15).Table 1: Differences among the three natural anticoagulantsBesides these actions, the interaction between anticoagulants and heparin seems to play a key role. It is known that heparin-bound AT cannot bind to GAG on EC (16, 17), and rTFPI can be displaced from EC by heparin (18). In contrast, the interaction between APC and heparin is not well defined. The effects of concomitant use of heparin in the clinical trials may be a critical factor and are discussed in a different section below. Differences of anticoagulatory and profibrinolytic effects The question “Does an improvement in hypercoagulopathy improve survival?” needs to be answered. In the PROWESS trial, a significant decrease of D-dimer was observed in the treatment group, and a beneficial effect on survival was found when the patient demonstrated DIC (19). In the KyberSept publication, this kind of parameter is not described. rTFPI treatment was associated with lower prothrombin fragment 1.2 and thrombin-antithrombin complex (TAT) levels at 24 and 96 h postinitiation of treatment in the OPTIMIST trial (P < 0.001). In contrast to the PROWESS trial, no apparent survival benefit was observed in this study. From these contrasting results, we feel it is difficult to conclude that an improvement of survival mainly depends on the correction of the coagulation disorder. Among the three drugs, only APC has a direct in vitro effect on fibrinolysis by inhibiting plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI). This action may be significant because the imbalance of coagulation/fibrinolysis is assumed to play a major role in the development of organ dysfunction (20). However, the connection between the anti-inflammatory or profibrinolytic effects of APC and the survival benefit is still unclear, and parts of the effects already described in the original publication have since been questioned by other investigators (21). The authors hope that this interesting question will be addressed in the near future. Differences in the kinetics of three natural anticoagulants Both protein C activity and AT activity significantly decrease during sepsis. Furthermore, numerous studies have revealed that a decreased level of these anticoagulants significantly correlates with the severity of sepsis (22-24). As a result, anticoagulant therapy was initially substitution therapy to correct the deficiency. The baseline protein C level decreased significantly in the PROWESS trial, 50% in the placebo and 47% in the rhAPC-treated patients. In the KyberSept trial, more than 50% of the patients presented with an AT level less than 60%. In contrast to those two anticoagulants, the circulating concentrations of rTFPI vary widely in patients with sepsis and the results are inconsistent (25, 26). DIFFERENCES OF THE THREE CLINICAL TRIALS Three trials were almost carried out for the same period. They are all randomized, placebo-controlled multicenter, phase III studies enrolling around 2000 subjects suffering from severe sepsis. In all trials, the subjects received either a placebo or the study drug for a period of 4 days. The primary endpoint in all trials was the “all-cause 28 day mortality” (Table 2).Table 2: Differences in the designDifferences in the baseline severity of the subjects One might ask if the severity of sepsis of the subjects enrolled in these trials was similar? Because the primary endpoint was mortality, the severity of disease of the subjects is a crucial aspect. When we compare the mortality rate in the placebo group, it was lowest in the PROWESS trial, highest in the KyberSept trial, and an intermediate rate in the OPTIMIST trial (Table 3). It might be understandable that the patients in the KyberSept trial were too severely ill to be successfully managed with any agent. However, Eichacker et al. (27) reported that anti-inflammatory agents were significantly more efficacious in patients at high risk of death. In addition, in a post hoc analysis of the data performed by the FDA anti-infective advisory committee investigating the efficacy of rhAPC in the PROWESS study (28), the benefits of rhAPC appeared to be restricted to patients with more severe illness [i.e., those with an Acute Physiology and Chronic Health Evaluation (APACHE) II score of 25 or more] (29). Interestingly, a similar finding was observed in KyberSept, and the 90-day mortality tended to decrease in patients belonging to the high-risk Simplified Acute Physiology Score version II (SAPS II) stratum. In the OPTIMIST study, the results were completely different. The overall mortality was lower in rTFPI-treated patients with a low APACHE II score ( 20; 38.8% in treatment group vs. 37.4% in placebo group), and this trend was more prominent when the patients were divided by the international normalized ratio (INR) of prothrombin time. The rTFPI-treated patients in the low-INR group (INR < 1.2) showed a better survival (mortality 12.0%) than the placebo group (mortality 22.9%). This beneficial effect was not recognized in the high-INR patients (34.2% of mortality in the treatment group vs. 33.9% of mortality in the placebo group). Although the last result opposed the former two, Freeman et al. (30) summarized 11 controlled studies and concluded that anticoagulants provide survival benefit when used as adjunctive therapy in sepsis if targeted to patients with high risk of mortality from this disease. The observation that AT did show the trend of favorable outcome in a high-risk group but not in the very high-risk group indicates that there should be an proper window regarding the severity for the each agent.Table 3: Differences in the resultsDifferences in the timing of the treatment Regarding the timing of the treatment, it is generally accepted that early initiation of therapy produces more favorable results. The timing was strictly regulated in the KyberSept trial. Subjects received either a placebo or AT within 6 h (plus another 2 h to obtain informed consent, etc.) if they met the inclusion criteria. Even though it is ideal, to have stricter timing of therapy than this design may be meaningless when we consider the clinical application. Differences of the dose of the agents ”Was the dose of AT and rTFPI sufficient?” is an important question to be addressed. When we consider the optimum dose of these agents, we should evaluate not only the anticoagulant effects but also the anti-inflammatory mechanisms. Furthermore, based on the pharmacokinetics of these agents, we also have to look not only at the activity in plasma but also at the localization of manifestation regarding the efficacy of these agents. Where is it localized? Is it in the plasma, on the endothelium, or extravascular? Together with the activity in plasma, the activity at the local site should be examined. A dose of 30,000 IU of AT was administered in the KyberSept trial, and mean AT activity reached 180% in 24 hours. Warren et al. mentioned that the increase in the AT activity was lower than expected (3, 31), and this insufficient dose might have been the cause of the negative results. However, 30,000 IU is a large amount of drug, and the costs approach that of rhAPC treatment. In addition, a significant bleeding tendency has been recognized with this dose of AT (RR 1.71; 95% CI 1.42-2.06) (Table 3). In contrast, an effective dose of rTFPI was used because phase II trials were carried out to determine the appropriate dose before the OPTIMIST trial started (32, 33). The effects of the synchronous use of heparin The concomitant prophylactic use (for purposes of venous thromboembolism prophylaxis) of low-dose unfractionated or low-molecular-weight heparin was allowed in all trials (Table 2). Did concomitant heparin abolish the anti-inflammatory effects? Even a prophylactic dose of heparin might affect the results, especially those targeted in the KyberSept and the OPTIMIST trial. AT and rTFPI must bind to GAGs on the EC surface to cause anti-inflammatory effects. However, if either AT or TFPI did react with heparin, its active site was blocked, and no further binding sites to the GAG on the endothelium are available. This seems to be confirmed by the results of the KyberSept and OPTIMIST trials because the favorable tendency in the treatment group, where no concomitant heparin was administered, disappeared once the treatment group also received heparin. The 28-day mortality in the subjects receiving high-dose AT without concomitant heparin was 37.8%, whereas the mortality in subjects receiving placebo without concomitant heparin was 43.6% (RR 0.86; 95% CI 0.73-1.02). In contrast, the mortality in subjects receiving AT or placebo together with concomitant heparin was 39.4% and 36.6%, respectively (RR 1.08; range 0.96-1.22). A similar result was obtained in the OPTIMIST trial. From these observations, even small doses of heparin, for example less than 15,000 IU/day, may counteract the anti-inflammatory effects of AT and rTFPI. Did administration of concomitant heparin increase the rate of adverse events? The question of whether administration of concomitant heparin increases the rate of adverse events is not clear. Probably yes in the case of AT, but unlikely in the case of rTFPI and rhAPC. In the KyberSept trial, the incidence of any bleeding in subjects enrolled in the treatment group, increased from 17.8% without concomitant heparin to 23.8% with the concomitant use of heparin. As a result, in addition to the potential abrogation of the anti-inflammatory effect of AT, heparin might enhance the bleeding tendency, and therefore, the beneficial effects of AT might be completely diminished. In contrast to this result, the trend was unclear in the OPTIMIST trial. In the high-risk group (INR > 1.2), the incidence of bleeding events in the treatment group was 23% with heparin and 28% without heparin (P < 0.03). In the PROWESS trial, heparin did not affect the incidence of bleeding (19). THE EFFICACY OF LOW-DOSE HEPARIN FOR SEVERE SEPSIS The question whether low-dose heparin was effective was raised (34). Regarding the results of the subgroup analyses of all three trials, the prophylactic use of heparin or the administration of low-molecular-weight heparin improved the survival if they were not used together with anticoagulants (Table 4). However, heparin use was not the intention-to-treat population (35), and it might be true that heparin was not applied to more severe cases such as those with increased bleeding tendency. We have to accept that heparin use was not randomized in these studies, and thus, we are not able to exclude a bias. A randomized double-blind, placebo-controlled study is needed to determine whether heparin has a beneficial effect. However, because rhAPC has become a standard choice for this situation (36), this type of study may not be feasible.Table 4: Survival at 28 days among patients with sepsis who received low-dose unfractionated or low-molecular-weight heparin as compared with those who did notPOTENTIAL ANTICOAGULANT THERAPY FOR SEVERE SEPSIS THAT REQUIRES INVESTIGATION Unexamined anticoagulants such as thrombomodulin and factor Xa inhibitor (37, 38) may be candidates for future studies. In addition, new heparinoids that do not block AT from binding to GAG on the endothelium and that do not maximize the bleeding tendency may also be investigated. Danaparoid sodium (DS) is a low-molecular-weight heparinoid with a mean molecular weight of approximately 6000 Daltons. It consists mainly of heparan sulfate and dermatan sulfate. The high-affinity fraction of the heparan sulfate inhibits factor Xa by catalyzing its binding to AT. Compared with unfractionated heparin, DS has a lower binding affinity for AT (39). The AT/DS combination therapy offers less bleeding, less affinity for AT, and may shift the antithrombotic activity from thrombin to factor Xa. Currently, these beneficial effects have been investigated in an animal model in our laboratory (40). SUMMARY The results of three megatrials investigating the potential beneficial effects of anticoagulant and anti-inflammatory substances in subjects suffering from severe sepsis have been published recently. rhAPC produced an improvement in survival, but AT and TFPI could not. The concomitant use of heparin might be responsible for this difference because a direct interaction exists between heparin and the latter two agents. Heparin-bound AT or rTFPI might have been unable to further bind to EC; thus, the anti-inflammatory function of these agents was canceled. In addition, heparin significantly increased bleeding events. Finally, we have to remember that although these therapies have the potential to improve the survival of severe sepsis/septic shock, the favorable effects come with the increase of bleeding tendency.