ECCMID 2018

Supplementary materials for ECCMID 2018 abstract 989:

Modelling the benefit of echocardiography in patients with Staphylococcus aureus bacteraemia at low risk of endocarditis: implications for future trials.

GS Heriot1, SYC Tong2, AC Cheng1, D Liew1
1School of Public Health and Preventative Medicine, Monash University,
2The Peter Doherty Institute for Infection and Immunity, University of Melbourne

Supplementary methods

Model specification
The underlying model for the Monte Carlo simulation is designed to examine the survival benefit of echocardiography for a patient with Staphylococcus aureus bacteraemia (SAB) who does not have an intracardiac prosthetic device (prosthetic valve, pacemaker or implantable defibrillator), clinical signs of endocarditis, or another reason for prolonged antibiotic therapy, and is assessed as having a less than 5% probability of endocarditis by one of a number of scoring systems1.

The model is based on three disease states: uncomplicated SAB, clinically occult S. aureus left-sided native valve endocarditis (NVIE) without perivalvular complications (abscess), and NVIE with perivalvular abscess formation. Echocardiographic assessment has the same three possible results, with the correlation between the actual diseases state and the echocardiographic result being dependent on the diagnostic performance of each echocardiography strategy. Transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE) are not assumed to be independent tests given the similarities between the two procedures. The degree of statistical covariance between these tests is described as the percentage of the maximal covariance allowed by the observed diagnostic performance statistics2.

Treatment decisions are based on the results of echocardiography alone: patients thought not to have endocarditis receive two weeks of parenteral anti-staphylococcal therapy; those thought to have uncomplicated NVIE receive six weeks of parenteral anti-staphylococcal therapy; and those thought to have NVIE complicated by perivalvular abscess receive six weeks of parenteral anti-staphylococcal therapy and remedial cardiac surgery (assumed to be valve replacement). No other indications for surgery are considered in the model as, by definition, patients do not have clinical signs of endocarditis (including heart failure and systemic emboli).

The two strategies without echocardiography result in all patients receiving antibiotic therapy for the duration specified without surgery for perivalvular abscess.

The outcome of the model is survival at 90 days. This outcome has been chosen to reflect the likely primary outcome of any future trial in this area to allow the model to inform statistical calculations. Survival outcomes in the model are additive. The expected survival resulting from any given strategy is the sum of the products of each possible permutation’s probability and its respective expected survival, as seen in the example decision tree presented in Figure 1.

Figure 1. Example decision tree and expected survival calculation used to model the outcome of each of the six echocardiography strategies.

Model inputs

Parameter estimates and error distributions were identified from the medical literature published to 16 November 2017 using a stepwise search strategy as outlined in a previous modelling paper3. These estimates are presented in Table 1.

Table 1. Parameter estimates, error distributions and sources.

Definition

Estimate

Range or 95% CI

Distribution

Sources

Probability of disease

Prevalence of clinically-occult endocarditis in patients with apparently-uncomplicated S. aureus bacteraemia (SAB) and no intracardiac prosthetic device

Variable

0-5%

 

1,4

Prevalence of perivalvular abscess among patients with clinically-occult native valve endocarditis (NVIE)

15%

10-20%

Triangular

5-9

Probability of relapse if clinically-occult left-sided NVIE treated with two weeks of parenteral antibiotic therapy

60%

40-80%

Triangular

10-18

Diagnostic performance of transoesophageal echocardiography (TOE)

Sensitivity of TOE for clinically-occult NVIE

96%

92-99%

Triangular

19-23

Specificity of TOE for clinically-occult NVIE

90%

90-95%

Triangular

19-23

Sensitivity of TOE for perivalvular abscess in patients with NVIE

75%

40-90%

Triangular

7,9,24-26

Specificity of TOE for perivalvular abscess in patients with NVIE

98%

96-100%

Triangular

7,9,24-26

Diagnostic performance of transthoracic echocardiography (TTE)

Apparent sensitivity of TTE for occult NVIE (as compared to TOE)

58%

53-62%

Beta

27

Apparent specificity of TTE for occult NVIE

92%

91-93%

Beta

17,18,27

Apparent sensitivity of TTE for perivalvular abscess

48%

29-67%

Beta

27

Apparent specificity of TTE for perivalvular abscess in occult NVIE

100%

99-100%

Beta

27

%maximum statistical covariance between TTE and TOE

25%

0-50%

Triangular

No data

Survival estimates for various diseases states

90-day survival of patients with apparently uncomplicated SAB

80%

76-83%

Beta

28

Excess mortality associated with diagnosed and treated NVIE

15%

10-25%

Triangular

29-31

Additional mortality associated with relapsed partially-treated NIVE

15%

12-17%

Triangular

32,33

Excess mortality associated with diagnosed and treated perivalvular abscess in NVIE

15%

0-30%

Triangular

5,7,34-36

Additional mortality if perivalvular abscess initially goes unrecognised

15%

0-30%

Triangular

5,7,34-36

Risks associated with testing and treatment

Excess mortality due to the procedures required for TOE

Variable

0.01-1%

 

37-40

Excess mortality due to the procedures required for TTE

0%

  

Assumed

Excess mortality due to adverse drug events in weeks 2-6 of therapy

0.2%

0-0.7%

Beta

41,42

Excess mortality due to line infection arising in weeks 2-6 of therapy

0.3%

0.1-0.8%

Beta

43-54

Excess mortality due to cardiac surgery for perivalvular abscess

5%

3-9%

Triangular

55,56

Multiple independent sources in general agreement with each other were found for each of these parameters, with three exceptions:

  1. As extensively discussed in a previous paper3, estimates for the procedure-related mortality of TOE vary from 0.01% to 1% depending on study methodology. This discrepancy is unresolvable with the currently available literature. As a result, we have chosen to report our results primarily as a two-way sensitivity (strategy) analysis, using the probability of endocarditis and the mortality of TOE as the variables.
  2. The likelihood of relapse if unrecognised clinically-occult S. aureus NVIE is treated with only two weeks of parenteral anti-staphylococcal therapy is essentially unknown. There are no studies examining the deliberate use of short-course therapy for left-sided endocarditis, and the available studies reporting relapses of endocarditis after the inadvertent use of abbreviated therapy do not provide a reliable denominator to assess how often this may occur.

    The estimate we have used for our analysis comes from dividing the relapse rate among unselected patients with central line-associated SAB treated with two weeks of antibiotic therapy (6%12) by the prevalence of endocarditis among such patients in series with high rates of TOE (10-15%14-16).

    In addition, we have assessed the impact of the traditional estimate for this parameter (100%13) in the sensitivity analyses presented below.

  3. The maximal statistical covariance (or non-independence) of TTE and TOE is also unknown, as there are no studies rigorously comparing the distribution of the results of both modalities against an independent reference standard (e.g. autopsy or surgical findings). Previous modelling studies57 have assumed these tests to be independent, but the similarities in technology (ultrasound) and target abnormalities (structural abnormalities of cardiac valves and associated structures) ensure some degree of correlation in their errors.

We have chosen to model a low but non-zero degree of non-independence between TTE and TOE (~25% the maximum possible statistical covariance) in our primary results, and a higher degree (~75%) in the sensitivity analysis presented below. The effect of these degrees of non-independence on the true diagnostic performance of TTE for NVIE can be seen in Table 2.

Table 2. Effect of non-independence of TTE and TOE on the true diagnostic performance of TTE for left-sided native valve endocarditis.

 

Sensitivity

Specificity

Performance of TOE for NVIE compared to pathological findings19

96%

90%

Apparent performance of TTE compared to TOE in series with 18% prevalence of NVIE27

58%

92%

True performance of TTE assuming:

  

Statistical independence of TTE and TOE

60%

93%

25% maximal statistical covariance

54%

90%

50% maximal statistical covariance

48%

88%

75% maximal statistical covariance

42%

85%

100% maximal statistical covariance

37%

83%

Sensitivity analyses

The effect of universal relapse of NVIE after short-course therapy

As described above, we estimated the proportion of cases of clinically-occult NVIE that would relapse after inadvertent receipt of two weeks of parenteral antibiotic therapy to be 60% (range 40-80%). Figure 2 shows the effect of assuming that all such patients would suffer relapses. The increased mortality associated with under-treatment of NVIE that results from this assumption causes a linear transformation in the horizontal axis compared to our base-case scenario.

Figure 2. Preferred echocardiography strategy assuming 100% relapse rate for NVIE after inadvertent short-course treatment.

The effect of high statistical covariance between TTE and TOE

As the degree of non-independence of TTE and TOE increases, the informational value of strategies employing two studies falls. Figure 3 shows the effect of assuming a high degree of correlation between the errors of TTE and TOE (75% maximal possible statistical covariance). TTE as the initial test followed by TOE if the TTE is positive no longer appears as a preferred strategy.

Figure 3. Preferred echocardiography strategy assuming a high degree of statistical covariance between TTE and TOE.

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