1. Update on better disease diagnosis
Update on better disease diagnosis
New markers in suspected acute coronary syndromes: Are they relevant for primary care?
Prof Frank Buntinx
Leuven, Belgium

2. Perceived needs of GPs
Clinical presentation of patients with chest pain in General Practice
Which markers are available?
Current diagnostic guidelines for chest pain patients
POCT
H-FABP studies
Results of the Genk study
Design of the GP-based study

3. POC tests: Perceived needs of European GPs
Preliminary results of an Internet questionnaire (2013) among 2067 GPs in UK, Belgium, the Netherlands.
GPs using or willing to use (if available) Troponine or H-FABP: 75%.
GPs desiring a POCT for diagnosing ACS: 4.4% (= top 5) Each GP could call max. 5 situations

4. Chest pain in a General Practice
5% of all patient contacts are related to chest pain.
Patients with chest pain in GP: 5 – 15 % has a CAD (ongoing IPD analysis 5 studies). In Flanders: 5% in GP (50% during an urgent house call), 24% in hospital A&E Dept.
These numbers differ between countries & settings.
Each GP will see patients with a serious chance to have a serious coronary problem. That will probably remain.

5. Time between start of symptoms & presentation
Hospital: 4,5 hrs (1-42 hrs)
General practice:
We don’t really know
Study ongoing

6. Diagnosing in a chest pain patient
Signs & symptoms are not sufficient (Bruyninckx ea meta-analysis BJGP 2009).
sensp = 0,94 (91-96)
PPV = 0.18 (LR+=2) – 25% (LR+=3)
ECG: even STEMI can initially be negative
Non-STEMI gives no typical changes
Biomarkers

7. Plasma marker proteins after AMI

8. Newer biomarkers Recently new biomarkers, especially hs-Troponines
Typical cut point for Troponines untill recently 100 pg/ml (hs-TnT Roche)
Recently cTnT with P 90 = 14 pg/ml
cTnI pg / ml
This resulted in new definitions of myocardial Infarction

9. *: initially or increase over 3 hours
Chest pain
symptoms
ECG
(hs-) Troponines
STEMI +
(initially -)
+ *
Non-STEMI -
Unstable angor
No coronary problem
*: initially or increase over 3 hours

10. H-FABP
All previously mentioned tests have too low sens / NPV when used early after start of symptoms.
Recently the H-FABP has been developed and tested as an alternative for Troponines.
Initial tests indicated that rise after start of the complaints would be earlier compared to Troponines (and therefore FABP would be interesting for first responders, typically GPs).

11. H-FABP
Requirements for a biomarker test for use in emergencies by a GP:
POCT
Providing a qualitative result
Fast: result in < 5 minutes
reliable
Small and light (to be carried in the doctor’s bag)
 no separate reading device
Easy to use
Low cost / reimbursed

12. What is currently available?
Older tests in different versions, even in combinations.
Troponines: different versions, but all with a cut-point at 100 pg/ml – or Cobas H 232 (Roche): 30 pg/ml POCT, but with result after 14 minutes
H-FABP:
Older version (Cardiodetect – cut-point = 7 ng/ml): has been tested in GP, clinical value was weak
Newer version at cut-point = 4 ng/ml; initial tests were very promising, currently being tested in Maastricht / Leuven.

13. FABPulous H-FABP True Rapid Test Design Concept
Lateral flow technique
1 drop - 4 minutes

14. Problems when using biomarkers in chest pain patients
False positives:
Other cardiac (e.g. heart failure) & non-cardiac (e.g. sepsis) disorders
Impaired renal function
(ageing)

15. Testing the H-FABP for use in GP: clinical testing strategy (RAPIDA)
Normal values studied in different age groups Glatz: P99 = 5,6 ng/ml.
Genk study (n=200 chest pain pat., consecutively admitted to a teaching hospital’s emergency department, Prev = 51%) / Quantitative results (ELISA):
Defining an optimal cut-point
Comparison Troponine – FABP results
Fine tuning of the POCT: design, user friendliness
General practice based diagnostic study in 600 consecutive chest pain patients

16. Results of the Genk study
First samples of all 218 patients
AUC:
FABP: 0,73
cTnt:
> 4,0: Sens = 0,75 Spec = 0,69 
> 5,6: Sens = 0,59 Spec = 0,83

17. Results of the Genk study
First samples of the patients: sensitivities
0,92
N° patients between % CI = +/- 10%

18. Results of the Genk study
First samples of the patients: NPV of H-FABP
patients
NPV (Prev = 17%)
NPV (Prev = 10%)
all
93,3
85,8
0-3 hrs
88,3
92,9
4-6 hrs
96,1
97,6
0-6 hrs
91,7
94,3
7-12 hrs
98,0
98,8

19. Conclusions
H-FABP (cut-off = 4 pg/ml) alone will probably not be able to reliably rule out AMI.
Combination of H-FABP and hs-TnT (both negative) is promising,
Combination with signs & symptoms has not been tested yet, but may be a very good test combination

20. Design of the GP-based study
600 consecutive chest pain patients.
Flanders and the Netherlands.
Each patient will have a POCT – FABP test + signs and symptoms + venous sample.
Outcome according to the ESC guidelines, but repeated Tnp only if hospitalized.
Analysis: Diagnostic accurracy indicators for FABP, Tnp, combination of FABP & Tnp, with and without signs & symptoms.
Start: September 2013

21. Discussion / comments
In a Swedish study with Cobas H232, GPs with the POCT performed worse than GPs without ! Cave false reassurance!!
False positive results are not dangerous, but they can have a negative impact if you intend to reassure your patient.
You always can improve sensitivity, but at the cost of false positives !!!
Discussion exists about the cut-point between MI and UA: A (slightly) positive initial biomarker result in a patient with UA may be an indicator that something is happening in the myocard. Initial study results suggest that prognosis of UA patients may be worse than MI.  Follow-up of Genk study patients is planned.
Normally a test result never stands alone, but adds to the clinical information. We don’t have signs & symptoms in the Genk dataset and therefore cannot study the incremental value of the test results. We will have this information in the GP study.