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Keywords:

  • Valproate;
  • Thrombocytopenia;
  • Gender effect;
  • Plasma level;
  • Platelet;
  • Antiepileptic drugs

Summary

  1. Top of page
  2. Methods
  3. Study Design
  4. Exclusion of Data
  5. Statistical Analysis
  6. Results
  7. Discussion
  8. References

Purpose: The frequency of valproate (VPA)-induced thrombocytopenia varied widely in previous studies, due to methodological differences. Our objective was to evaluate the relationship between trough VPA plasma levels and platelet counts and assess risk factors for the development of thrombocytopenia.

Methods: Patients with refractory partial epilepsy were enrolled in this double-blind, multicenter, concentration–response trial that evaluated the efficacy and safety of high versus low trough plasma VPA concentrations following administration of divalproex sodium as monotherapy. Trough VPA concentrations and concomitant platelet counts were drawn at baseline and intermittently throughout the 24-week trial. Bivariate correlations and multivariate stepwise regression analysis were performed between platelet counts and multiple variables. A logistic regression analysis was done to determine the probability of developing thrombocytopenia at various VPA levels.

Results: A total of 851 VPA levels and concomitant platelet counts were analyzed in 265 patients. Of these, 17.7% of patients experienced at least one episode of thrombocytopenia (platelet count ≤ 100,000/μl) after exposure to divalproex sodium. A significant negative correlation was found between VPA levels and platelet counts. Women were significantly more likely to develop thrombocytopenia. The probability of developing thrombocytopenia substantially increased at trough VPA levels above 100 μg/ml in women and above 130 μg/ml in men.

Discussion: Our data strongly support a causal relationship between rising plasma VPA levels and reduced platelet counts, with additional risk factors including female gender and lower baseline platelet counts.

Divalproex sodium (DVPX) is an antiepileptic drug (AED) approved as monotherapy and add-on therapy for the treatment of complex partial seizures, as a prophylactic agent for migraine headaches, and for the treatment of acute manic episodes in patients with bipolar disorders. Similar to many drugs, valproate (VPA) is associated with idiosyncratic reactions as well as dose-related side effects. The latter includes weight gain, hair thinning, tremor, and thrombocytopenia (Beydoun et al., 1997). The frequency of VPA-induced thrombocytopenia has varied widely in previous reports, mostly due to methodological disparities (Richardson et al., 1976; Von Voss et al., 1976; Winfield et al., 1976; Raworth and Birchall, 1978; Neophytides et al., 1979; Coulter et al., 1980; Loiseau, 1981; Barr et al., 1982; Hoffman, 1982; Ganick et al., 1990; Tohen et al., 1995; Allarakhia et al., 1996; Anderson et al., 1997; Conley et al., 2001; Trannel et al., 2001).

In this study, we prospectively evaluated a cohort of patients who participated in a randomized, double-blind, multicenter, concentration–response design clinical trial evaluating the safety and efficacy of DVPX sodium as monotherapy for the treatment of partial epilepsy. The objective of the study was to evaluate the possible relationship between trough VPA plasma levels and platelet counts, and to assess risk factors for the development of thrombocytopenia.

Methods

  1. Top of page
  2. Methods
  3. Study Design
  4. Exclusion of Data
  5. Statistical Analysis
  6. Results
  7. Discussion
  8. References

Patients, 10–75 years of age, with a diagnosis of localization-related epilepsy and a documented history of at least two complex partial seizures per month while maintained on one AED (carbamazepine, phenytoin, primidone, or phenobarbital) at therapeutic plasma concentrations were eligible to participate in this study. Patients previously exposed to DVPX and who failed to respond at plasma VPA levels greater than 40 μg/ml (275 mmol/L; conversion factor: VPA level in mmol/L = 6.94* VPA level in μg/ml) or with a history of intolerance to the drug were excluded. Also excluded were pregnant women, women of childbearing potential not practicing adequate birth control, patients with generalized seizures in the previous 2 years, and those with a history of pseudoseizures or noncompliance. Additional exclusion criteria included patients with CNS neoplasm, active CNS infection, demyelinating disease, degenerative neurological disease, or any progressive CNS disease. In addition, patients with metabolic, gastrointestinal, renal, hepatic, or hematopoietic disease were excluded. Also excluded were patients with medical or neurological disorder, other than epilepsy, likely to require changes in medications, including dosage changes. Patients who required therapy with anticoagulant drugs or aspirin were excluded, as were patients with psychiatric disorder, alcoholism, drug abuse, or drug addiction.

Study Design

  1. Top of page
  2. Methods
  3. Study Design
  4. Exclusion of Data
  5. Statistical Analysis
  6. Results
  7. Discussion
  8. References

This was a randomized, double-blind, parallel group, multicenter, concentration–response design trial that compared the safety and efficacy of high (80–150 μg/ml) and low (25–50 μg/ml) target trough plasma VPA concentrations in patients with complex partial seizures treated with DVPX as monotherapy (Beydoun et al., 1997). The Institutional Review Board at each center approved the study protocol, which was conducted in compliance with the U.S. Food and Drug Administration regulations. More details about the protocol design were previously published (Beydoun et al., 1997).

Patients were randomly assigned in a 1:1 ratio at each center into the high (80–150 μg/ml) or low (25–50 μg/ml) target trough plasma VPA concentration groups. The study consisted of a baseline phase lasting 8–12 weeks, and a 24-week double-blind experimental phase. The experimental phase was divided into a dosage adjustment period (first 8 weeks) followed by a 16-week dosage maintenance period. During the dosage adjustment period, the baseline AED was tapered and treatment with DVPX was initiated. DVPX dosage was gradually titrated upward to achieve the maximum tolerated plasma concentration within the targeted range for each patient. To enter the 16-week maintenance period, patients had to be completely withdrawn from their baseline AED and treated with DVPX as monotherapy. During this phase of the protocol, DVPX dosage was adjusted based on efficacy and tolerability while maintaining trough plasma VPA within the targeted ranges.

Trough plasma VPA concentrations and platelet counts were determined from analysis of blood samples collected either 8–15 h after the last DVPX dose or less than 1 h after the first dose of the day (taken before noon). Platelet counts were measured during the baseline phase, every 2–4 weeks during the dosage adjustment period, and every 8 weeks thereafter. Trough plasma VPA levels were measured at every visit. All laboratory values were analyzed at a central laboratory. In this study, we defined clinically relevant thrombocytopenia as a platelet count of 100,000/μl or less (Wyngaarden et al., 1992).

Exclusion of Data

  1. Top of page
  2. Methods
  3. Study Design
  4. Exclusion of Data
  5. Statistical Analysis
  6. Results
  7. Discussion
  8. References

For each patient, we included all paired data consisting of trough plasma VPA levels and concomitant platelet count. For some patients, the dose of DVPX was reduced during the double-blind phase because of adverse events, leading to a drop of more than 20% in plasma VPA levels. To avoid a spurious association between plasma VPA levels and platelet counts, data including and subsequent to this drop were excluded.

Statistical Analysis

  1. Top of page
  2. Methods
  3. Study Design
  4. Exclusion of Data
  5. Statistical Analysis
  6. Results
  7. Discussion
  8. References

Bivariate correlations between platelet counts after exposure to DVPX and multiple variables, including duration of DVPX exposure, trough plasma VPA concentration, patient's age, and baseline platelet counts, were performed. A multivariate stepwise regression analysis was done to determine the significant variables in this group. A logistic regression analysis was carried out to determine the probability of developing thrombocytopenia at particular trough plasma VPA levels. Values of significance were set at p < 0.05.

Results

  1. Top of page
  2. Methods
  3. Study Design
  4. Exclusion of Data
  5. Statistical Analysis
  6. Results
  7. Discussion
  8. References

Demographics

Of the 305 patients who signed an informed consent and were enrolled in the baseline phase of the study, 265 qualified for randomization in the double-blind phase. Of the 265 patients, 134 and 131 were randomly assigned to the low- and high-concentration groups, respectively. There were 144 (54%) women and 121 (46%) men with a mean age 34.5 years. During the baseline phase, the majority of patients were receiving carbamazepine or phenytoin as monotherapy. The average DVPX dose during the double-blind phase was 16.5 mg/kg/day in the low-dosage group and 40.3 mg/kg/day in the high-dosage group. The most common classes of comedications taken during the trial were analgesics, antipyretics, nonsteroidal antiinflammatory drugs, H1 receptor antagonists, and nasal decongestants. Those medications were equally distributed between patients randomized to the high and low VPA concentration groups.

Platelet count

A total of 851 trough plasma VPA levels and concomitant platelet counts were analyzed. The mean trough plasma VPA level was 79.6 μg/ml (range 13.00–257.00 μg/ml) and the mean baseline platelet count was 272,000/μl (range 125,000–478,000/μl) (Fig. 1A).

imageimage

Figure 1. (A) Histograms showing the baseline platelet counts and (B) the platelet counts following exposure to DVPX.

The platelet count dropped to a mean of 215,000/μl (range 16,000–439,000/μl) after exposure to DVPX (Fig. 1B). The mean reduction from baseline platelet count was 57,000/μl (range –122,000 to 329,000/μL) and was significantly higher than zero (t-test, p < 0.01) (Fig. 2).

image

Figure 2. Histogram showing the distribution of drop in platelet counts following exposure to DVPX.

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Occurrence of thrombocytopenia

Forty-seven (17.7%) patients with a mean age of 34 years (range 10–64 years) experienced a total of 71 episodes of thrombocytopenia (platelet count ≤ 100,000/μl). Of the 131 patients randomized to the high VPA concentration group, 41 (31%) developed thrombocytopenia compared to 6 out of 134 patients (4%) randomized to the low VPA concentration group (χ2, p < 0.001). Thrombocytopenia occurred on average 82 days (range 38–170 days) after exposure to DVPX. In those 71 episodes, the mean platelet count was 72,000/μl, with a range between 16,000/μl and 100,000/μl. The corresponding mean trough plasma VPA level was 141 μg/ml (range 77–243 μg/ml).

VPA levels and platelet counts

The frequency of thrombocytopenia increased with higher plasma VPA level. Table 1 stratifies the frequency of thrombocytopenia according to various plasma VPA level ranges.

Table 1.  Stratification of frequency of thrombocytopenia according to various trough plasma VPA level ranges
VPA level (μg/ml)NFrequency of thrombocytopeniaPercentage
<80479 1 0.2
81–100109 5 4.6
101–120 911314.3
>1201725230.2
Total85171 8.3

Using univariate analysis, significant correlations were found between platelet count and trough VPA plasma level (Pearson correlation =–0.61, p < 0.01) (Fig. 3), duration of VPA exposure (Pearson correlation =–0.44, p < 0.01), and baseline platelet count (Pearson correlation = 0.43, p < 0.01). Of the 131 patients randomized to the high VPA concentration group, 54 had a baseline platelet count of less than 250,000/μl, while 87 had a platelet count equal or greater than 250,000/μl. Thrombocytopenia occurred in 22 (41%) of the 54 patients with a baseline platelet count less than 250,000/μl compared to 19 (22%) of 87 patient with a platelet count equal or greater than 250,000 (p = 0.05).

image

Figure 3. Linear regression of platelet counts versus trough VPA plasma levels with 95% confidence intervals. There was a significant negative correlation that best fitted the following formula: Expected platelet count = 297 – (1.03 * VPA trough level); (r =–0.61, p < 0.01).

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The only significant variables in a multiple stepwise regression analysis were the trough plasma VPA levels and baseline platelet counts. The linear relationship was as follows:

Expected platelet count = 138 – (1.055 * trough VPA level) + (0.593 * baseline platelet count) (p < 0.001).

Logistic regression

A logistic regression was done to evaluate the probability of developing thrombocytopenia at particular trough plasma VPA levels (Fig. 4). Based on this model, the probability of developing a platelet count of 100,000/μl or less was

image

Figure 4. Probability of developing a platelet count ≤100,000/μl at various trough plasma VPA levels for the whole group of patients (middle line) and for women and men analyzed separately.

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Ln (p/(1 – p)) = (0.0353 * VPA trough level) – 6.1611

Where Ln is the natural log and p is the probability of developing a platelet count of 100,000/μl or less.

The logistic regression model based on our data had a 91% predictive value.

Gender effect

The baseline platelet count was similar in women (271,000/μl) and men (272,000/μl) (t-test, p > 0.1). The frequency of thrombocytopenia was significantly higher in women. Thirty-six women compared to 11 men experienced thrombocytopenia (χ2 test; p = 0.001). The frequencies of thrombocytopenic episodes in men and women stratified according to various trough plasma VPA ranges are shown in Table 2. Thrombocytopenic episodes were significantly more frequent in women trough VPA plasma levels greater than 100 μg/ml (p < 0.01).

Table 2.  Stratification of frequency of thrombocytopenic episodes according to various trough plasma VPA level ranges in men and women
VPA level (μg/ml)MenWomen
NEpisodes of thrombocytopenia (%)NEpisodes of thrombocytopenia (%)
<802210 (0)257 1 (0.4)
81–100 52 1 (1.9) 574 (7)
101–120 390 (0) 5213 (25)
>120 85 14 (16.5) 87 38 (43.7)

Based on this finding, we performed separate stepwise multiple regression analysis for women and men with the following results:

Expected platelet count in women = 127 – (1.156 * trough VPA level) + (0.656 * baseline platelet count) (p < 0.001)

Expected platelet count in men = 155 – (0.929 * trough VPA level) + (0.503 * baseline platelet count) (p < 0.001)

In addition, the logistic regression analysis to determine the probability of developing a platelet count of 100,000/μl or less for a given trough plasma VPA level was performed separately for women and men (Fig. 4) with the following results:

Ln (p/(1 – p)) for women = (0.0451 * VPA trough level) – 6.7126 (predictive value 89%)

Ln (p/(1 – p)) for men = (0.0295 * VPA trough level) – 6.4851 (predictive value 96%)

The probability of developing thrombocytopenia appeared to substantially increase at trough VPA levels above 100 μg/ml in women and above 130 μg/ml in men (Fig. 4).

Age effect

We stratified the frequency of thrombocytopenia in various age groups according to trough plasma VPA levels (Table 3). As can be seen from Table 3, with similar mean plasma VPA concentrations, the percentage of patients who developed thrombocytopenia was comparable across all age groups.

Table 3.  Stratification of frequency of thrombocytopenia according to various trough plasma VPA level ranges in various age groups
Age (years)NPatients with thrombocytopenia (%)Mean VPA level (range) μg/ml
<20 34 6 (18%)76 (13–174)
20–3914527 (19%)81 (13–257)
40–59 7413 (18%)78 (13–243)
≥60 121 (8%)80 (23–197)

In addition, a bivariate correlation showed no significant association between the platelet count after exposure to DVPX and age.

Adverse events related to thrombocytopenia and premature withdrawals

No patient with thrombocytopenia required transfusions or died because of low platelet count. Fourteen patients (5.3%) prematurely exited the trial primarily due to thrombocytopenia. A total of seven patients exhibited bleeding complications such as petechia, ecchymosis, excessive menstrual flow, hemorrhagic colitis, and hematemesis. Those bleeding complications were reported by the investigators on the adverse events forms and were categorized as possibly related to thrombocytopenia. Five of those patients prematurely exited the trial.

There was no significant difference in the platelet count nadir between the patients with bleeding complications and those without (t-test, p > 0.1). The average nadir platelet counts were 60,000/μl (range 16,000–75,000/μl) and 48,000/μl (range 26,000–74,000/μl) in patients with bleeding complications and those without, respectively. For patients with bleeding complications, the baseline platelet count was 241,000/μl (range 167,000–337,000/μl) and the mean age was 28.5 years (range 16–49). For patients without bleeding complications, the corresponding values were 272,000/μl (range 157,000–380,000/μl) and 38.4 years (range 20–57).

All patients with thrombocytopenia recovered from this adverse event after dose reduction or discontinuation of DVPX.

Of the 40 asymptomatic patients with thrombocytopenia, 9 patients prematurely exited. There was a significant difference in the platelet nadir count between asymptomatic patients who prematurely withdrew and those who did not. The mean nadir platelet count was 48,000/μl on those who prematurely withdrew, and 79,000/μl in those who did not (t-test, p < 0.001). It appears that the threshold of platelet count of less than 60,000/μl was felt to be clinically relevant by the investigators since 67% of asymptomatic patients who prematurely exited had a platelet count of less than 60,000/μl compared to 6% of asymptomatic patients who continues in the trial (Fisher's test, p = 0.001).

Discussion

  1. Top of page
  2. Methods
  3. Study Design
  4. Exclusion of Data
  5. Statistical Analysis
  6. Results
  7. Discussion
  8. References

Our study unequivocally demonstrates an association between DVPX therapy and thrombocytopenia. In addition, the significant negative correlation between VPA plasma levels and platelet counts strongly supports a causal relationship between rising trough plasma VPA concentration and lowering of platelet count.

In previous studies, the reported frequencies of VPA-induced thrombocytopenia have varied greatly, and ranged from 0% to 32% (Richardson et al., 1976; Von Voss et al., 1976; Winfield et al., 1976; Raworth & Birchall, 1978; Neophytides et al., 1979; Coulter et al., 1980; Loiseau, 1981; Barr et al., 1982; Hoffman, 1982; Ganick et al., 1990; Tohen et al., 1995; Allarakhia et al., 1996; Anderson et al., 1997; Conley et al., 2001; Trannel et al., 2001). Various factors likely contributed to this wide variability in reported frequencies, including the definition of thrombocytopenia (which ranged between 100,000 and 200,000/μl), the retrospective nature of most studies (Raworth & Birchall, 1978; May & Sunder, 1993; Delgado et al., 1994; Tohen et al., 1995; Allarakhia et al., 1996; Conley et al., 2001), the small number of patients evaluated and the fact that most patients were receiving low to moderate daily doses of VPA. For instance, in a large retrospective study of 1,251 patients treated with VPA, no patient with a platelet count below 100,000 was reported (Tohen et al., 1995). However, the daily VPA doses or plasma levels achieved in those patients was not documented (Tohen et al., 1995).

The strength of our study is that this is the first double-blind trial that allowed the prospective evaluation of patients on gradually increasing dose of DVPX taken as monotherapy. The sequential assessment allowed us to analyze the effect of a wide range of VPA plasma levels on platelet counts. Our results indicate that the overall frequency of thrombocytopenia (platelet counts ≤ 100,000/μl) was 17.6%, but that it increases exponentially with progressively higher trough plasma VPA levels. Whereas the likelihood of developing thrombocytopenia is negligible at trough plasma VPA level of ≤80 μg/m (0.4%), the frequency increased to 5.1%, 12.8%, and 30.2% at trough plasma VPA levels of 80–100 μg/ml, 100–120 μg/ml, and >120 μg/ml, respectively. Although one could arguably have used another cutoff point for the definition of thrombocytopenia, we chose a value of 100,000 to represent a clinically relevant reduction in platelet count (Wyngaarden et al., 1992). Our finding of a VPA plasma level dependent reduction in platelet count is consistent with some previous retrospective studies that tried to correlate platelet count with VPA dosage or random VPA plasma level (Neophytides et al., 1979; Delgado et al., 1994; Gidal et al., 1994; Allarakhia et al., 1996; Hauser et al., 1996; Verotti et al., 1999). A concentration–response design is a better method than a dose–response design because the latter does not take into account the interindividual variablity in age, weight, or absorption and rate of elimination of the study drug. Indeed, studies have shown that specific doses of DVPX produce a wide range of plasma VPA concentration in different patients (Loiseau et al., 1975; Wulff et al., 1977; Levy, 1984).

Our data indicate that in susceptible patients, thrombocytopenia tends to develop quickly following exposure to high plasma VPA levels. The mean time from DVPX exposure to the first observed episode of thrombocytopenia was 82 days (range 38–170 days), a period which included the 8-week titration phase. It is likely that the true onset was sooner, but was first observed at this time point due to the intermittent nature of platelet count monitoring. Previous studies have indicated that the interval between the initiation of VPA treatment and platelet nadir is variable among patients who develop thrombocytopenia, ranging from 8 days to 16 months (Barr et al., 1982; Delgado et al., 1994). Other studies have shown that thrombocytopenia tends to develop promptly when the VPA dosage or plasma VPA level are above certain critical values (Raworth & Birchall, 1978; Hoffman, 1982). Because of its relatively short duration, we cannot exclude the possibility that the frequencies reported in our study could be an underestimate of the true frequency of thrombocytopenia at particular serum levels.

The mechanism of VPA-induced thrombocytopenia is unclear. The possibilities include a dose-dependent suppression of bone marrow production of platelets or peripheral platelet destruction due to the development of a platelet antibody brought about by VPA or one of its metabolites. Favoring the peripheral platelet destruction hypothesis, Barr et al. (1982) reported that 82% of cases of VPA-induced thrombocytopenia were associated with an increased platelet-related immunoglobulin level, and that the platelet count was inversely correlated to the concentration of platelet-related immunoglobulin (Barr et al., 1982). It was suggested that the structural similarity between VPA and the fatty acid constituents of cell membranes may lead to an increased incidence of immune thrombocytolysis (Sandler et al., 1978; Morris et al., 1981). The reported finding of normal or slightly increased levels of megakaryocytes in bone marrow examination of patients with VPA-induced thrombocytopenia is also consistent with increased peripheral platelet destruction (Neophytides et al., 1979). This hypothesis does not however adequately explain the rapid reversal of thrombocytopenia after reduction of VPA dosage (Delgado et al., 1994). Kishi et al. (1994) have shown that a high plasma VPA concentration is associated with in vivo and in vitro bone marrow suppression. While the VPA concentration-dependent thrombocytopenia could be explained by the mechanism of bone marrow suppression, the rare occurrence of pancytopenia suggests that other mechanisms must be involved that renders the platelet cell lineage more vulnerable to VPA suppression or damage (Robinson et al., 1995; Oluboka et al., 2000). It is possible that both immune-mediated peripheral destruction and VPA concentration-dependent suppression of platelet precursors may be operating simultaneously.

Another very interesting and previously unreported finding is the dramatic difference in gender risk for the development of thrombocytopenia. We found that women were significantly more likely to develop thrombocytopenia compared to men. The probability of developing thrombocytopenia appears to substantially increase at trough VPA levels above 100 μg/ml in women and above 130 μg/ml in men. A recent study has shown a significantly higher female overrepresentation in heparin-induced thrombocytopenia, with females at approximately twice the risk for heparin-induced thrombocytopenia compared to males (Warkentin et al., 2006). Although the underlying mechanism for this gender difference is unclear, it could be that the immune system of women is more adept in generating a DVPX-induced thrombocytolysis or that women are more susceptible to DVPX-induced bone marrow suppression.

Some have reported that the elderly is more prone to develop thrombocytopenia after exposure to VPA (Conley et al., 2001; Trannel et al., 2001). Our data do not support this assertion, since the frequency of thrombocytopenia in patients 60 years of age or older was not higher than that of younger age groups despite very similar mean trough VPA plasma levels across the age groups. The relatively small number of elderly patients in our study does not however allow for a more categorical statement regarding this issue.

Although DVPX-induced thrombocytopenia was generally asymptomatic, 7 of 47 thrombocytopenic patients developed symptoms possibly related to low platelet count. This is consistent with a previous study that reported that 8 of 64 patients with VPA-associated thrombocytopenia developed signs of bleeding (Delgado et al., 1994). VPA-induced thrombocytopenia was reversible in all our patients following dose reduction or discontinuation, a finding consistent with a number of previous studies (Neophytides et al., 1979; May & Sunder, 1993; Delgado et al., 1994).

There is considerable disagreement in the literature about the evidence of a relationship between plasma VPA levels and therapeutic effect (Turnbull et al., 1983). The so-called therapeutic range for VPA of 50–100 μg/ml (345–695 mmol/L) was based on two small poorly controlled studies of patients on polytherapy (Schobben & Van Der Kleijn, 1974; Vajda et al., 1976). It is frequently necessary to achieve plasma levels above 70 μg/ml (485 mmol/L) to control partial-onset seizures (Turnbull et al., 1983; Beydoun et al., 1997). In these patients, the platelet count should be monitored, and one can expect a high frequency of thrombocytopenia, especially in women or at plasma levels higher than 100 μg/ml. In these patients, the importance of regularly monitoring platelet counts should be stressed, and patients should be advised to watch for and immediately report easy bruising and bleeding.

Disclosure of conflict of interest: The authors report no conflicts of interest.We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Methods
  3. Study Design
  4. Exclusion of Data
  5. Statistical Analysis
  6. Results
  7. Discussion
  8. References
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