Summary and general discussion
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1 Chapter 7 Summary and general discussion
2 Summary and general discussion In this thesis, treatment of vitamin K antagonist-associated bleed with prothrombin complex concentrate was addressed. In this we focused on finding the optimal, cost-effective, and safe prothrombin complex concentrate dose strategy. Summary In chapter 2, as a pilot, we explored the feasibility of a simple, low fixed prothrombin complex concentrate dose strategy. We used a before-and-after design, taking advantage of a change in local dosing protocol. Consecutive patients receiving prothrombin complex concentrate were enrolled in two cohorts in which either a fixed dose (cohort 1) or a variable dosing based on bodyweight, initial INR and target INR was applied (cohort 2). Patients with an intracranial hemorrhage were excluded. The primary end point was the proportion of patients who achieved the target INR within 20 minutes after prothrombin complex concentrate was infused. In cohort 1, 70% of patients (21 out of 30) and in cohort 2, 80% (22 out of 27) of patients reached the targeted INR (P=0.37). Although a numerically lower proportion of patients reached the targeted INR in cohort 1, a positive clinical outcome was equally seen in both cohorts (91% in cohort 1 versus 94% in cohort 2, P=1.0). The positive clinical outcome was defined as any visual bleed that stopped, and/or no further need for blood or more prothrombin complex concentrate transfusion, and/or no further fall in hemoglobin. The equal clinical outcome in this pilot study was reached with significantly lower dosages of prothrombin complex concentrate in the fixed dose cohort. With the knowledge that INR is not validated in overanticoagulation and therefore might not be a reliable indicator for reversal, we did a post-hoc analysis on patients with an initial INR above and under 5. The difference in reaching the target INR, as mentioned above, was only applicable to those patients with an initial INR above 5. In patients with an initial INR below 5, target INR was equally reached with a low fixed dose as with higher, variable dosages. However, even for patients with an initial INR above 5 no 128
3 Chapter 7 difference in positive clinical outcome was seen (15 out of 17, 88% in fixed dose versus 14 out of 15, 93% in variable dose strategy). The finding that clinical outcome was not always related to the INR was rather interesting in a landscape in which the goal of prothrombin complex concentrate treatment has always been to restore INR to normal levels. This finding suggests that the positive clinical outcome could be the result of the earlier initiation of treatment with a fixed dose rather than the actual dosage. Infusion with a fixed prothrombin complex concentrate dose could theoretically start sooner than a variable dose because of the need to know initial INR and patients weight before the variable dose can be calculated. In chapter 3, efficacy and safety of a fixed prothrombin complex concentrate dose was prospectively evaluated in a two parallel cohorts design. In this, non-inferiority of the fixed dose was hypothesized with a margin of 4% for the proportion of patients reaching the target INR. We enrolled consecutive patients with a major vitamin K antagonist associated bleed in two hospitals in The Hague. These patients were either treated by the low fixed dose or a more widely used variable INR- and weight-dependent prothrombin complex concentrate dosing strategy. Again, we found that target INR was reached in fewer patients treated with a fixed dose (92%) compared to the variable dosing regimen (95%). Hence, based on INR, non-inferiority of fixed dose was not established. However, positive clinical outcome was significantly more often observed in the fixed dose (96%) compared to the variable dose regimen (88%, P<0.001). Planned subgroup analysis showed that in proportion of patients with an initial INR below 5, target INR is reached equally with the fixed dose as with the variable dose regimen (46 out of 46 patients in fixed dose versus 51 out of 52 patients in variable dosing regimen). Furthermore, post-hoc analysis showed that the inferiority of the fixed dose in terms of reaching the targeted INR only accounts for those patients with an initial INR above 7.5. For these selected patients, target INR was reached in 28 out of 30 patients (80%) with the fixed dose versus 41 out of 45 patients (91%) with the variable dosing regimen. However, even in this proportion of patients, 129
4 Summary and general discussion positive clinical outcome was seen more often in the fixed dose cohort compared to the variable dose cohort. This specific finding confirmed our earlier (chapter 2) suggestion that clinical outcome is not necessarily related to restoring the INR to normal levels. As we made the assumption that speed of reversal might be very essential to clinical outcome in chapter 2, we prospectively measured time from presentation to emergency room until infusion of prothrombin complex concentrate in this chapter. Time to infusion appeared to be 30 minutes shorter when a fixed dose strategy was applied (130 minutes versus 160 minutes, P<0,05). Hereby, we confirmed that time to infusion is shorter when a fixed dose is applied. However, its implication for clinical outcome should be furthermore investigated as our study was not designed to address this question. Overall, based on this study we conclude that the non-inferiority of the low fixed dose strategy of prothrombin complex concentrate is not established in terms of reaching the target INR. However, regarding clinical outcome significantly more patients were successfully treated with a low fixed dose compared to the higher variable regimen. In chapter 4, we addressed an important question from both a clinical and financial point of view that rose after having performed the previous study: are additional interventions needed when a low prothrombin complex concentrate fixed dose is used to reach a non-inferior outcome when compared to a variable dosing regimen? We studied this by performing a cost study on data derived prospectively for patients who had been enrolled in our previous study. To prevent bias in estimating the costs of VKA-related bleeds we excluded patients already hospitalized for other indications and evaluated the direct medical costs only in patients who were admitted through the emergency department. Therefore, direct medical costs were evaluated in 137 patients (59 in fixed dose and 78 in variable dosing cohort). In this we used two decision tree models. In model A reaching the target INR was modeled while model B was only based on the clinical outcome. Furthermore, the sensitivity was analyzed using three worst-case scenarios. Direct medical costs during hospitalization from ER admission to discharge 130
5 Chapter 7 or death, including costs for prothrombin complex concentrate and blood transfusion, endoscopic and/or surgical treatment, mortality, medical ward and/or intensive care stay, were taken into account. In summary, our cost analyses showed that a cost reduction in prothrombin complex concentrate with a low fixed dose strategy did not coincide with a cost increase due to utilization of other treatment options for VKA associated bleedings. Furthermore, by treatment of these bleeding emergencies with a low fixed prothrombin complex concentrate dose strategy, on average 1634 per patient to 2100 per successfully treated patient was saved compared to a variable dosing strategy. The robustness of this finding was confirmed in sensitivity analyses. Costs should not be the driving force behind selecting the right treatment. However, taking costs into account is becoming increasingly important when choosing between alternatives. Especially since prothrombin complex concentrate usage is more and more being explored for counteraction of the newer oral anticoagulant therapy. In chapter 5 we performed a review of the literature. By systematically gathering data we aimed to describe the current stage of research with regard to the search for the optimal dosing strategy for prothrombin complex concentrate. We included 28 prospective prothrombin complex concentrate studies that used dosing strategies based on body weight, body weight and initial INR, body weight and initial INR and target INR, a regimen where the dose was left to the discretion of the physician (doctors decision strategy,) or a fixed dose strategy. Studies were predominantly small, single-arm and open-label with at most moderately robust study designs. Our review showed a great diversity in dosing protocols (15 different dosing protocols). Moreover, many different definitions for assessing the outcome of prothrombin complex concentrate treatment for both target INR as well as clinical outcome were used indicating the lack of consensus regarding different aspects of emergency reversal of VKA treatment. This concerned six different primary end points: the proportion of patients reaching a target INR in 16 studies (57%), INR decrease in 4 (14%), incidence of thromboembolic complications in 2 (7%), clinical response in 3 (11%), appropriate PCC 131
6 Summary and general discussion treatment in 2 studies (7%) and 1 study with co-primary endpoints existing of clinical response and reaching target INR (4%). In addition, twelve different definitions were used for the above mentioned primary endpoints. Firstly, target INR as a primary endpoint was 1.5 in 6 studies, 1.3 in three studies, 3.5 and 2 in one study each or it was differentiated in two or more target INRs (e.g. partial or complete reversal) in 6 studies. Secondly, incidence of thromboembolic events as a primary endpoint was either reported as occurrence of thromboembolism within 7 or within 30 days after PCC administration. Thirdly, appropriate PCC treatment was defined as adherence to a national guideline in one study and defined by the authors in another study. Lastly, clinical response definition ranged from cessation of bleed in one study, intracranial hematoma enlargement in another study to no further bleeding complications in the third study. In the fourth study in which clinical response counted as a co-primary endpoint, a hemostatic efficacy scale was developed in discussion with the Food and Drug Administration. Despite the heterogeneity, we pooled data and performed minimal analyses, which led to two main findings: firstly, having a predefined dosing protocol is essential as any dosing strategy appeared to show better outcome results compared to the strategy in which the treating physician is supposed to decide on the dosing for each individual patient. Secondly, lowest prothrombin complex concentrate dosages are applied when using fixed dose protocols (median dosage of 1000 IU factor IX per patient). In this, no difference in outcome was seen when compared to strategies in which higher doses were used. In chapter 6, patients who survived a vitamin K antagonist-related major bleed in the study described in chapter 3 were followed to determine their long term outcome in terms of incidences of (fatal) thromboembolism, recurrent (fatal) bleed and mortality. In addition, we characterized patients who either continued or discontinued the vitamin K antagonist therapy. 189 patients were followed for a total of 362 patient-years (median of 23 months). Vitamin K antagonist was restarted in the majority of patients (n=140, 74%), whereas it was discontinued after the index bleed for the 132
7 Chapter 7 remaining 49 (26%) patients. Discontinuation of VKA seemed to be based on patients health status, only discontinuing therapy in more severely ill patients. Older age and a history of major bleeds were not taken into account in the restart decision making. Incidence of major rebleed was very high (29 per 100 patient-years) and the main predictor for future bleeds appeared to be a history of more than 1 major bleed. Clearly, our study demonstrated a vulnerable VKA population characterized by a very high rebleed-risk. It should be further investigated whether and to what extent this main predictor of future bleeds could play a role in the decision making in VKA restart policy after a major bleed has occurred. Although we observed a better survival for patients who restarted VKA therapy after the index bleed in a multivariable survival analysis, we cannot make recommendations based on this finding. After all, this could well be explained by bias by indication. General discussion and future perspectives Management of vitamin K associated major bleed is a continuing clinical challenge. Although through the years the effectiveness and safety of prothrombin complex concentrate has been subjected to many trials, an optimal dose strategy in relation to cost-effectiveness and safety is still lacking. In this thesis, we investigated the feasibility of a relatively simple fixed dose regimen for prothrombin complex concentrate compared to a variable dosing regimen based on patient s weight, initial INR and the targeted INR. This simple fixed dose seemed promising as the dosage is lower than the variable dosing regimen, whereas the same positive clinical outcome is gained. Furthermore, it appeared to be a cost saving strategy. However, in both our pilot study as well as in the prospective trial, target INR was not equally reached in patients presenting with a high initial INR (INR above 5 in the pilot study and above 7.5 in the next trial). However, results of clinical outcome were significantly better for these patients in the fixed dose cohort. Additionally, time to infusion was significantly shorter in the fixed dose cohort. This parameter could be the reason for positive 133
8 Summary and general discussion clinical outcome when fixed doses are applied. Obviously, this should be further investigated. Furthermore, future investigation should eliminate other limitations of our previous studies from which the non-randomized setting was the most important one. At this moment we are preparing a protocol for future study of prothrombin complex concentrate in emergency reversal of VKA associated major bleeds. In this future study, our goal is to assess superiority of the fixed dose regimen in a randomized, multicenter setting. For such a study approximately 400 patients over 8 clinical centers are needed. As shorter time to infusion was our main ground for clinical outcome of the fixed dose, our biggest challenge will be not to delay or diminish any time to infusion because of the clinical investigation setting and patient randomization. In our pilot and prospective study, we faced the lack of correlation between clinical outcome and reached INR. Time to infusion rather than the reached INR after treatment seemed to correspond with clinical outcome. Despite years of experience with prothrombin complex concentrate for emergency reversal of vitamin K antagonists, many aspects regarding assessment of treatment outcome still lack consensus. In our review, the majority of studies (57%) used the reached INR as a primary endpoint to assess prothrombin complex concentrate s effectiveness. However, the target INR to be reached varied enormously among these studies. As INR is an objective parameter and easy to assess, it is understandable that this parameter was preferably used by most investigators as a primary parameter. However, there is no evidence for the correlation between reached INR and clinical outcome and what level of INR restoration is needed for a successful clinical outcome. Moreover, in daily practice, clinical outcome should be leading and all effort should be made to standardize the definition of clinical outcome in prothrombin complex concentrate treatment for future studies. In the Scientific Subcommittee on Control of Anticoagulation of the International Society on Thrombosis and Haemostasis (ISTH) we will discuss this topic and propose development of a unified and practical formulation for clinical outcome after treatment of a major bleed. This definition should be 134
9 Chapter 7 applicable for treatment of both old and new oral anticoagulant-associated bleeds as well as all other agents to which the definition of major bleed applies. In our follow-up study we demonstrated a considerably higher risk of future bleeds after a VKA-associated major bleed had occurred. In this study, continuation of VKA therapy after treatment of such a major bleed was to the discretion of the treating physician. However, the treating physician faces a strong dilemma whether or not to discontinue VKA as there could be a possible shift in balance between risk of stroke towards risk of recurrent major bleeds. While in daily practice patients health status, and potentially life-expectancy, appears to be the main parameter for this decision making, identifying those patients who are at higher risk of future bleeds could support this process. In today s practice, patients with bad health status discontinue VKA therapy after a first major bleed. For future studies, it would be of interest to know whether these patients would benefit from VKA continuation after a major bleed to prevent from having a (fatal) thromboembolic event. Furthermore, future research should address whether the proportion of patients at highest risk for major rebleed (those with a history of more than 1 major bleed) would take advantage of discontinuation of VKA after a major bleed has occurred. However, the bottom line is that once a major bleed has occurred, the outcome is unfavorable in terms of future bleeds and mortality. Promising oral alternatives for VKA have entered daily clinical practice. These novel oral anticoagulants (NOACs) show an overall decrease of major bleeds compared to VKA in clinical trial setting. Of course, these trials commit to strict settings in which patients are highly selected. Therefore, their efficacy and safety in large daily practice has still to be established compared to VKA. Furthermore, these novel drugs lack specific antidotes. At this time, usage of prothrombin complex concentrates is one of the main options when confronted with a NOAC-associated major bleed. High quality clinical data are still lacking in this field, no trials have been performed. Hopefully, the many registers that are being started will collect useful clinical 135
10 Summary and general discussion data about this treatment. Of course, specific antidotes for NOACs are being developed. However, until then and so far, it is essential to gain knowledge about the most rational way to dose prothrombin complex concentrates for emergency treatment of any anticoagulant associated bleed. In our search for the optimal, cost-effective, and safe prothrombin complex concentrate dosing strategy, the present thesis has added important data to today s knowledge. Firstly, it shows the unreliability of INR in relation to clinical outcome when higher initial INR is involved. Secondly, speed of reversal is highly suggested to be the main ground for a successful treatment. Thirdly, prothrombin complex concentrate treatment with a low fixed dose seems feasible in clinical practice. Finally, lowest effective dosages seem to be infused when a fixed dose is applied. 136
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