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Previous Volume 330:1864-1869 June 30, 1994 Number 26 Next

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ABSTRACT

Background It is uncertain whether patients with proximal deep-vein thrombosis should be treated with streptokinase followed by intravenous heparin or with intravenous heparin alone. Published reports indicate that streptokinase plus heparin increases the risk of bleeding, including central nervous system bleeding and death, but decreases the risk of postphlebitic syndrome. Previous recommendations regarding these treatments have not considered patients' preferences or the values they attach to the possible outcomes of therapy.

Methods We used decision analysis to combine published estimates of the probabilities of various adverse outcomes of treatment (bleeding, pulmonary embolism, postphlebitic syndrome, and death) with the values patients placed on these outcomes. We questioned 36 patients about the values they attached to each outcome. Sixteen patients had had deep-vein thrombosis, and 20 had not.

Results By the values they attached to the outcomes, all 36 patients indicated that they were unwilling to accept an increased risk of death to avoid postphlebitic syndrome. According to the decision analysis, heparin alone was the better treatment for all 36 patients. As compared with streptokinase plus heparin, heparin alone provided 29 days of additional life expectancy over the predicted life expectancy of 20 years. Although the difference between the two treatments was small, heparin alone remained the better treatment in sensitivity analyses that examined the reasonable ranges of probabilities of the clinical outcomes.

Conclusions The values patients placed on the outcomes of treatment for deep-vein thrombosis support the use of heparin alone over the combined use of streptokinase and heparin.

Methods

Review of Published Articles

We conducted a Medline search of articles published from 1968 through 1993, using the following key words: heparin, streptokinase, thrombolysis, deep-vein thrombosis, clinical trials, prospective trials, and reviews. We also searched bibliographies. We selected only studies dealing with proximal lower-extremity deep-vein thrombosis. We evaluated a total of 30 studies.

Decision Model

The decision model appears in Figure 1, showing potentially adverse outcomes of streptokinase and heparin that are well described in the literature: anaphylaxis (principally with streptokinase), major bleeding, pulmonary embolism, and postphlebitic syndrome. Decisions about treatment, possible events, and outcomes are shown. The overall outcome of the model is quality-adjusted life expectancy, calculated by multiplying patients' life expectancies¹² by the values they assign to the outcomes they experience.

View larger version (15K): [in this window] [in a new window]   Figure 1. Decision Tree. The open box at left indicates the initial decision regarding treatment. Open ovals denote chance events, and solid rectangles outcomes. CNS denotes central nervous system.

 
Probability of Adverse Outcomes

We used a meta-analysis of randomized trials comparing 72 to 96 hours of treatment with streptokinase plus heparin with heparin alone in order to estimate the probability of major bleeding⁶. We used data from randomized and nonrandomized trials of similar doses of streptokinase and heparin for the treatment of deep-vein thrombosis in order to estimate the probabilities of pulmonary embolism, central nervous system bleeding, and death from central nervous system bleeding^{1,2,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30}. We used trials involving the treatment of cardiovascular disease with thrombolytic agents to support our estimates of the risk of anaphylaxis, central nervous system bleeding, and death from central nervous system bleeding^31,32,33,34. The relative risk of postphlebitic syndrome after treatment with streptokinase was estimated from the data in one randomized trial¹³.

Patients' Stated Preferences Regarding Outcomes

Patients were asked to use the "standard gamble" to quantitate the strength of their preferences with respect to specific outcomes³⁵. First, they were asked to rank the outcomes from the best to the worst. Next, they were asked to consider the following choice: a gamble between the best and worst possible outcomes and a certain intermediate outcome. The patients were told that if they took the gamble and won, they would be ensured the best outcome, but that if they lost, they would be ensured the worst outcome. The probability of winning the gamble was repeatedly changed until the patient was indifferent to the choice between the gamble and the intermediate outcome. The probability of winning the gamble at this point of indifference was used to represent the value the patient attached to the outcome. If a patient was indifferent to the choice between the intermediate outcome (such as postphlebitic syndrome) and a 90 percent chance of the best outcome (good health) and a 10 percent chance of the worst outcome (death), the value for the intermediate outcome was considered to be 0.90.

Thirty-six patients were interviewed, all of whom were over the age of 50. Of these, 20 patients had not had deep-vein thrombosis and were chosen randomly from patients awaiting general medical appointments. They were given descriptions, derived from clinical trials, of the outcomes of therapy. Central nervous system bleeding was described as a stroke that would alter their ability to care for themselves. Mild postphlebitic syndrome was described as mild, persistent edema with minimal effects on lifelong activities. Severe postphlebitic syndrome was described as edema or leg ulceration causing chronic, lifelong discomfort.

To determine whether patients with postphlebitic syndrome might assign different values to the clinical outcomes, we interviewed 16 patients with this syndrome who were randomly chosen from a data base of such patients. Eleven met the criteria for mild postphlebitic syndrome; five met those for the severe syndrome. These patients were asked to express their preferences for outcomes using the standard gamble but were asked to consider their own postphlebitic syndrome as the intermediate outcome.

Assumptions about the Model

In constructing the model, we assumed that the diagnosis of deep-vein thrombosis was a definite one. We further assumed that anaphylactic reactions with streptokinase would necessitate switching to heparin. In addition, we assumed that no other risks or benefits of streptokinase would be incurred in the event of anaphylaxis. We considered only major bleeding, and the only consequence of major bleeding we included was bleeding of the central nervous system. Finally, we evaluated only patients without pulmonary embolism at the time of presentation.

Sensitivity Analysis

We evaluated all the variables over the entire range of values.

Results

Review of Published Articles

The results of the review of published articles are shown in Table 1.

View this table: [in this window] [in a new window]   Table 1. Base-Line Probabilities and Relative Risks of Selected Outcomes in Published Studies of Patients Treated for Deep-Vein Thrombosis.

 
Anaphylaxis occurred in 0.3 percent of the patients treated with streptokinase. There were no deaths from anaphylaxis^{1,13,15,16,17,18,19,20,21,22,23,24,25,26,27,33}. None of the patients treated with heparin had anaphylaxis.

Major bleeding occurred in 4.6 percent of the patients treated with heparin alone in the randomized trials of deep-vein thrombosis^{13,15,17,18,21,23,29}. In other randomized trials comparing heparin administered by continuous infusion with heparin administered by intermittent bolus, major bleeding occurred in 6.7 percent of the patients receiving a continuous infusion (95 percent confidence interval, 4.3 to 9.1)^{36,37,38,39,40,41,42}. We used 4.6 percent as our base-line estimate. The increased relative risk of major bleeding with streptokinase has been described in a meta-analysis; it was 2.9 (95 percent confidence interval, 1.1 to 8.1)⁶.

Central nervous system bleeding also occurred more often with streptokinase plus heparin than with heparin alone. In randomized trials of deep-vein thrombosis, one patient (0.9 percent) receiving streptokinase had central nervous system bleeding, as compared with no patients receiving heparin alone^{13,15,17,18,21,23,29}. In both randomized and nonrandomized trials, the probability of central nervous system bleeding was 1.3 percent (8 of 617 patients) with streptokinase plus heparin and 0.2 percent (1 of 453 patients) with heparin alone. We used the lower estimate of 0.9 percent for streptokinase plus heparin and the higher estimate of 0.2 percent for heparin alone as our base-line estimates.

Fifty-six percent of the patients with central nervous system bleeding (five of nine) died in the randomized and nonrandomized trials of deep-vein thrombosis. Therefore, the absolute chance of death from central nervous system bleeding was 0.5 percent (56 percent of 0.9 percent) for streptokinase plus heparin and 0.1 percent (56 percent of 0.2 percent) for heparin alone.

Pulmonary embolism occurred in 5.4 percent of the patients treated with streptokinase plus heparin (6 of 112) and 3.7 percent of those treated with heparin alone (4 of 109) in the randomized trials. In all the trials, the probability of pulmonary embolism was 4.5 percent among 617 patients treated with streptokinase plus heparin and 5.5 percent among 453 patients treated with heparin alone. We chose 5 percent as the base-line estimate for both therapies. Fourteen percent of the patients with pulmonary embolism died, regardless of therapy. Therefore, the absolute chance of death from pulmonary embolism was 0.7 percent for both treatments.

Five reports presented data on postphlebitic syndrome^{10,13,14,28,29}. Three studies were follow-up reports on patients previously enrolled in randomized trials,^10,14,28 but unfortunately there were no systematic rules for including patients. Only 60 percent of the patients treated with streptokinase and 55 percent of the patients treated with heparin alone were ever evaluated for postphlebitic syndrome. Since the potential for selection bias was considerable, we excluded the results of these three studies in estimating the probability of postphlebitic syndrome.

Two other studies^13,29 were prospective, but one included only 10 patients, 4 of whom did not have proximal lower-extremity deep-vein thrombosis²⁹. In the other prospective study, 38 patients (20 assigned to streptokinase and 18 to heparin alone) were followed for a mean of 19 months to assess the occurrence of postphlebitic syndrome¹³. The syndrome occurred in 40 percent of those treated with streptokinase plus heparin and 90 percent of those treated with heparin alone (relative risk, 0.44; 95 percent confidence interval, 0.26 to 0.78). Severe postphlebitic syndrome (with ulceration) did not occur in any patient treated with streptokinase, but it did occur in 5.6 percent of the patients treated with heparin alone (1 of 18).

Decision Analysis

Table 2 shows the incidence of central nervous system bleeding and postphlebitic syndrome per 10,000 patients treated. For every adverse outcome with streptokinase, 60 patients were spared mild postphlebitic syndrome and 7 were spared the severe syndrome.

View this table: [in this window] [in a new window]   Table 2. Incidence of Central Nervous System Bleeding and Postphlebitic Syndrome per 10,000 Patients Treated for Deep-Vein Thrombosis.

 
Table 3 shows the values patients attached to various outcomes. The mean values for mild and severe postphlebitic syndrome were each nearly 1.0. This means that our patients were willing to accept only small risks of death to avoid the postphlebitic syndrome. The values expressed by patients with postphlebitic syndrome and by those without it did not differ significantly. Ten patients considered central nervous system bleeding to be as bad as death.

View this table: [in this window] [in a new window]   Table 3. Mean Values Assigned to Selected Outcomes by Patients with and without Postphlebitic Syndrome.

 
We calculated quality-adjusted life expectancy using the patients' mean values for outcomes. We assumed a 20-year life expectancy after deep-vein thrombosis and shortened the life expectancy only if the patient survived central nervous system bleeding (excess death rate per year, 0.221)⁴³. With heparin alone there were 19.72 quality-adjusted years, as compared with 19.64 with streptokinase plus heparin (a difference of 29 days in life expectancy).

Sensitivity Analysis -- Patients' Values

Figure 2 shows the effect of a change in the value a patient assigned to severe postphlebitic syndrome. As this value decreases (indicating that the patient perceives severe postphlebitic syndrome to be more undesirable), the benefit achieved with heparin alone declines. The value for severe postphlebitic syndrome would have to fall below 0.90 (i.e., a patient would have to be indifferent to a gamble in which there was at least a 10 percent chance of death) before therapy with streptokinase plus heparin became the better choice. No patient reported a value below 0.90. Similarly, the value for mild postphlebitic syndrome would have to fall below 0.985 before treatment with streptokinase plus heparin became the more desirable therapy. No patient reported a value this low.

View larger version (12K): [in this window] [in a new window]   Figure 2. Sensitivity Analysis of the Values Assigned by Patients to Severe Postphlebitic Syndrome. As the values attached to severe postphlebitic syndrome decrease, the quality-adjusted life expectancy of patients treated with heparin alone declines. The preferred therapy is indicated by the shaded area. The value at which the benefits of the two therapies are equivalent is 0.90. Streptokinase plus heparin is the better treatment only below this value. The mean value assigned to severe postphlebitic syndrome by our patients was 0.982 (dashed line).

 
Because the efficacy of treatment in preventing postphlebitic syndrome was estimated from only one study, we examined the effects of changes in efficacy and in the probability of postphlebitic syndrome. If the efficacy of streptokinase is only 50 percent (the base-line value was 100 percent) and the probability of postphlebitic syndrome with heparin alone is also 50 percent, then a patient's value for severe postphlebitic syndrome would have to be lower than 0.71 before streptokinase plus heparin became the better choice. Clearly, this was below the values any of our patients indicated.

Sensitivity Analysis -- Risk of Major Bleeding

Figure 3 shows the effect of variation in the risk of major bleeding with streptokinase plus heparin. As the relative risk increases, the benefit declines because of the increase in central nervous system bleeding. Above a relative risk of 1.6, heparin alone is the better treatment. Even with a 100 percent chance of postphlebitic syndrome with heparin alone, the relative risk would have to be lower than 1.7 before streptokinase plus heparin became better. The only way that the values indicated by our patients would support an increase of 2.9 in the relative risk of major bleeding while receiving streptokinase plus heparin would be if the probability of major bleeding with heparin alone fell below 1.9 percent (base-line estimate, 4.6 percent).

View larger version (15K): [in this window] [in a new window]   Figure 3. Sensitivity Analysis of the Relative Risk of Major Bleeding Associated with Streptokinase. Heparin alone provides the better therapy if the relative risk of major bleeding with streptokinase plus heparin exceeds 1.6. The relative risk of major bleeding with streptokinase plus heparin (2.9) derived from published sources is indicated by the dashed line, and the preferred therapy by the shaded area.

 
Sensitivity Analysis -- Pulmonary Embolism and Excess Death Rate with Severe Postphlebitic Syndrome

The probability of pulmonary embolism or death from pulmonary embolism during treatment with streptokinase plus heparin must be equivalent to 60 percent of the probability with heparin alone before streptokinase plus heparin becomes the better choice of treatment. If the probability of dying from pulmonary embolism is lower than 8.7 percent (base-line estimate, 14 percent), then treatment with heparin alone is better, even if streptokinase is 100 percent effective at preventing death from pulmonary embolism.

We assumed that patients with postphlebitic syndrome would have a normal life expectancy. However, streptokinase plus heparin would constitute better treatment if a patient's life expectancy was reduced by at least 1.8 years by the presence of severe postphlebitic syndrome.

Discussion

We used decision analysis to examine which treatment -- streptokinase plus heparin or heparin alone -- is optimal for the treatment of deep-vein thrombosis. We included patients' preferences with respect to the outcomes of therapy and found that heparin alone was the preferred treatment.

The decision to use heparin alone was a close call; this regimen increased life expectancy by only 29 days. However, our assumptions favored streptokinase plus heparin. First, we considered only major bleeding, with central nervous system bleeding as the only consequence of major bleeding. We ignored minor bleeding and the deaths and disabilities associated with other types of major bleeding, all of which are more common with streptokinase plus heparin. The choice of heparin alone would be stronger if we included these additional adverse outcomes.

Second, we assumed that the diagnosis of deep-vein thrombosis is proved. If this is not true, then some patients who received streptokinase plus heparin would have no benefit because there would be no thrombosis. Yet these patients face an increased risk of major bleeding. If clinicians are not completely certain about the diagnosis of deep-vein thrombosis, that uncertainty makes heparin alone an even better choice.

Third, we used the average value that the patients placed on surviving central nervous system bleeding (0.29). However, 10 of our patients considered surviving such bleeding to be as bad as death; this makes heparin alone an even better choice for these patients.

Fourth, we chose the most advantageous probabilities for outcomes with streptokinase plus heparin and the least advantageous probabilities for outcomes with heparin alone. We chose the lowest estimate for the probability of central nervous system bleeding with streptokinase and the highest estimate with heparin. On the other hand, we considered streptokinase completely effective in reducing severe postphlebitic syndrome. These outcomes represent the key trade-offs involved in this decision. Even under these circumstances, heparin alone was the better choice.

Our estimates of the probabilities of pulmonary embolism and death from pulmonary embolism also favored streptokinase plus heparin. These estimates were high. If the probability of having pulmonary embolism or dying of it was reduced by 60 percent with streptokinase plus heparin, then that therapy was the better choice. There is no clear evidence, however, that streptokinase actually lowers the probability of pulmonary embolism, and if a hemodynamically important pulmonary embolism should occur during therapy for deep-vein thrombosis, the drug may be given at that time⁴⁴. In addition, if the probability of dying of pulmonary embolism is less than 8.7 percent, as some data suggest,^44,45,46 then heparin alone is always better, even if streptokinase is completely effective in preventing death. Although streptokinase plus heparin may prevent death from pulmonary embolism, this benefit occurs so infrequently that it cannot offset the increased risk of dying from central nervous system bleeding.

Finally, we chose a high estimate of the probability of postphlebitic syndrome in patients receiving heparin therapy alone (90 percent). If the risk of this syndrome after such treatment is less than 90 percent, then heparin alone becomes an even better choice.

Our analysis shows that patients consider postphlebitic syndrome trivial as compared with the risk of death. Yet this is the dilemma that patients face in deciding between these therapies. All the patients in our study indicated that avoiding an early death is more important than preventing an outcome that affects the quality of life. This insight was expressed even by the patients with postphlebitic syndrome. Previous studies have shown that values placed on outcomes differ between those who have and those who do not have the conditions in question⁴⁷. In contrast, we found similar values for postphlebitic syndrome expressed in our patient population whether or not the syndrome was present.

Our analysis yields treatment recommendations that differ from those made previously, which were made without explicit consideration of the values patients associated with specific outcomes. In our view, when patients face possible death during a period of treatment intended to prevent undesirable outcomes in the future, decisions about treatment should be made only after explicitly considering the patients' values. Otherwise, decisions may be made that are not in the best interests of the patients.

One of the limitations of our analysis is that we obtained information on treatment preferences from only 36 patients, all of whom were more than 50 years old. It is possible that patients with different characteristics may express values favoring treatment with streptokinase plus heparin. Therefore, we can make no statement about the treatment of choice for all patients. Another limitation is that we did not survey patients who had deep-vein thrombosis at the time they made their decisions. Patients who face a decision directly may assign different values to the possible outcomes. Nor is the best way to elicit patients' feelings about values clear. Our method incorporates the risk patients face in making such decisions, but there are other ways of assessing values that yield different results^35,47,48. It is not clear which method is best.

Our analysis underscores the importance of considering patients' values and preferences in making decisions about treatment. Even when estimates of the risks and benefits of particular treatment options are not well established, knowledge of patients' values may suggest the best decision.

Source Information

From the Divisions of General Medicine and Clinical Epidemiology (J.J.O., R.A.M., A.T.E., S.W.M.) and the Department of Pediatrics (S.M.D.), University of North Carolina at Chapel Hill, Chapel Hill.

Address reprint requests to Dr. McNutt at 5025 Old Clinic Bldg., Campus Box 7110, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7110.

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