Prevalence of PAH in SSc

Reference Methodology Diagnosis PAH prevalenceMukerjee; 2003, UK

• n = 722, single center• Prospective 1998-2002 RHC 12%

Hachulla; 2005, France

• n = 599, multi-center• Prospective, cross sectional RHC 8%

Phung; 2009, Australia

• n = 184, single center• Prospective, cross sectional RHC 13%

Vonk; 2009,Netherlands

• n = 819, multi-center• Prospective 2005-2007 RHC 9,9%

RHC: Right heart catheterization.

1. Mukerjee D, et al. Ann Rheum Dis 2003; 62:1088-93. 2. Hachulla E, et al. Arthritis Rheum 2005; 52:3792-800.

3. Phung S, et al. Intern Med J 2009; 39:682-91,4. Vonk MC, et al. Ann Rheum Dis 2009; 68:961-5

Diagnosis of PAH

PAH is defined as – mPAP ≥ 25 mmHg at rest, assessed by right heart

catheterization

– Pulmonary capillary wedge pressure ≤ 15 mmHg

– PVR > 3 Wood units (240 dyn sec/cm∙ 5)

Galiè N, et al. Eur Heart J 2009; 30:2493-537.McLaughlin VV, et al. Circulation 2009; 119:2250-94.mPAP: Mean pulmonary arterial pressure.

Existing screening recommendations

Proposed criteria for referral for right heart catheterization

ESC / ERS1

TR velocity sPAP Additional signs of PH on echo

Symptoms SSc

> 3.4 m/s > 50 mmHg Yes / No Yes / No Yes / No

2.93.4 m/s 3750 mmHg Yes / No Yes Yes

≤ 2.8 m/s ≤ 36 mmHg Yes Yes Yes

ACCF / AHA2 High right ventricular systolic pressure or right heart chamber enlargement on echocardiography

ACCP3 Clinical suspicion of PAH: echocardiography to evaluate level of right ventricular systolic pressure and abnormalities (right atrium or right ventricle enlargement and pericardial effusion)

Dana Point4 No recommendation

ESC / ERS, European Society of Cardiology / European Respiratory Society; ACCF / AHA, American College of Cardiology Foundation / American Heart Association; ACCP, American College of Chest Physicians

1Galiè et al. Eur Heart J 2009; 2McLaughlin et al. J Am Coll Cardiol 2009; 3Badesch et al. Chest 2007; 4Badesch et al. J Am Coll Cardiol 2009.

TR, tricuspid regurgitant jet; sPAP, pulmonary artery systolic pressure; PH, pulmonary hypertension

Background

PAH is the leading cause of death in SSc patients1,2

Screening may lead to earlier diagnosis and intervention and thus to improved outcomes

Current screening is based on consensus rather than robust evidence

No single laboratory test is shown to be adequate

PAH, pulmonary arterial hypertension; SSc, systemic sclerosis

1Steen and Medsger. Ann Rheum Dis 2007; 2Tyndall et al. Ann Rheum Dis 2010.

Rationale

TR velocity is main basis of ESC / ERS screening recommendations but– Does not accurately reflect invasive pressures1,2

– Is not present in all patients1

– PAH symptoms as additional criteria are open to interpretation

False positives are common particularly in ILD No systematic right heart catheterization (RHC) in any

screening study to date– Missed diagnoses rate (false negatives) could never be calculated

1Fisher et al. Am J Respir Crit Care Med 2009; 2Parent et al. N Engl J Med 2011.

ILD, interstitial lung disease; RHC, right heart catheterization

Objective of DETECT

To develop an evidence-based screening algorithm for PAH in SSc patients

Minimize the number of missed PAH diagnoses

Optimize the use of screening modalities

Optimize the use of diagnostic RHC

Design and methodology

Patient population– Aged ≥ 18 years

– SSc of > 3 years’ duration from first non-Raynaud feature

– DLCO < 60% of predicted

Prospective cross-sectional study design– RHC performed in all patients following collection of all

other data Demographics, medical history, physical exam, serum lab,

pulmonary function tests, ECG, echocardiography

DLCO, diffusing capacity of the lung for carbon monoxide; ECG, electrocardiography

Patient disposition

SSc patients screenedn = 646

RHC analysis setn = 466

Screen failures (n = 158)No RHC (n = 22)

PH: n = 145* (31%) mPAP ≥ 25 mmHg

Non-PH: n = 321 (69%) mPAP < 25 mmHg

WHO group 1 PH (PAH): n = 87 (19%)PCWP ≤ 15 mmHg

WHO group 2 PH (left heart disease): n = 30 (6%)PCWP > 15 mmHg

WHO group 3 PH (lung disease / hypoxia): n = 27 (6%)PCWP ≤ 15 mmHg

FVC < 60% or 6070% + HRCT not available or ‘moderatesevere’*PH classification not possible in one patient due to a missing pulmonary capillary wedge pressure (PCWP). mPAP, mean pulmonary arterial pressure; WHO, World Health Organization; FVC, forced vital capacity; HRCT, high resolution computed tomography

Patient demographics and characteristics

Non-PH (n = 321) PAH (n = 87)Male 16.6 25.6Age, years 54.7 ± 11.8 61.1 ± 9.8SSc

Duration, monthsDiffuse / limited / mixed or overlap

130.2 ± 96.136.5 / 54.3 / 9.2

163.0 ± 130.320.9 / 70.9 / 8.1

6MWD, m* 412.5 ± 107.2 389.7 ± 106.6WHO functional class

I/II vs. III/IV 83.7 / 16.3 64.4 / 35.6DLCO % predicted 48.0 ± 9.2 43.3 ± 10.5Right heart catheterization

mPAP, mmHgPCWP, mmHgPVR, dyn·sec/cm5

Cardiac index, L/min/m2

17.6 ± 3.88.5 ± 3.6

145.4 ± 64.63.0 ± 0.7

32.5 ± 8.310.3 ± 3.2

370.6 ± 225.82.9 ± 0.6

Data are mean ± standard deviation or %; *n = 243 / 66. 6MWD, 6-minute walk distance; PVR, pulmonary vascular resistance

DETECT: statistical analyses – variable selection

Final

Multivariable regression

across groupsMultivariable regression

within groups of variables

Expert selection: Clinically relevant and feasible variables

Descriptive statistics and univariable regression

Demographic and clinical parameters

(n = 68)

Serum tests(n = 13)

ECG parameters(n = 3)

Echocardiographic parameters

(n = 28)

112 variables

8 variables

DETECT: The 8 variables in the final screening algorithm

Non-PH PAH P-value* ROC AUC (95% CI)

FVC % pred. / DLCO % pred. 1.8 ± 0.5 2.2 ± 0.7 < 0.001 0.715 (0.656, 0.774)

Current or past telangiectasias 67.9 87.4 < 0.001 0.597 (0.554, 0.641)

Serum ACA positive 25.2 50.0 < 0.001 0.624 (0.564, 0.684)

Serum NTproBNP, log10

(pg/mL)2.1 ± 0.5

(230.0 ± 538.6)2.4 ± 0.5

(516.4 ± 805.0)< 0.001 0.675 (0.609, 0.742)

Serum urate, mg/100 mL 4.7 ± 1.5 5.9 ± 1.5 < 0.001 0.719 (0.659, 0.779)

Right axis deviation# on ECG 3.4 13.3 0.001 0.549 (0.511, 0.587)

Right atrium area, cm2 13.4 ± 4.7 17.1 ± 6.2 < 0.001 0.712 (0.650, 0.773)

TR velocity, m/s 2.4 ± 0.6 3.0 ± 0.8 < 0.001 0.795 (0.737, 0.853)

Data are mean ± standard deviation or %; *Wald 2 test; #QRS axis ≥ 90; ROC AUC, area under the receiver operating characteristic curve; ACA, anticentromere antibody; NTproBNP, N-terminal pro-brain natriuretic peptide

DETECT: The 8 variables in the final screening algorithm

Non-PH PAH P-value* ROC AUC (95% CI)

Step 1 0.844 (0.795, 0.898)

FVC % pred. / DLCO % pred. 1.8 ± 0.5 2.2 ± 0.7 < 0.001 0.715 (0.656, 0.774)

Current or past telangiectasias 67.9 87.4 < 0.001 0.597 (0.554, 0.641)

Serum ACA positive 25.2 50.0 < 0.001 0.624 (0.564, 0.684)

Serum NTproBNP, log10

(pg/mL)2.1 ± 0.5

(230.0 ± 538.6)2.4 ± 0.5

(516.4 ± 805.0)< 0.001 0.675 (0.609, 0.742)

Serum urate, mg/100 mL 4.7 ± 1.5 5.9 ± 1.5 < 0.001 0.719 (0.659, 0.779)

Right axis deviation# on ECG 3.4 13.3 0.001 0.549 (0.511, 0.587)

Step 2 0.881 (0.824, 0.923)

Right atrium area, cm2 13.4 ± 4.7 17.1 ± 6.2 < 0.001 0.712 (0.650, 0.773)

TR velocity, m/s 2.4 ± 0.6 3.0 ± 0.8 < 0.001 0.795 (0.737, 0.853)

Data are mean ± standard deviation or %; *Wald 2 test; #QRS axis ≥ 90; ROC AUC, area under the receiver operating characteristic curve; ACA, anticentromere antibody; NTproBNP, N-terminal pro-brain natriuretic peptide

DETECT: two-step screening algorithm

PAH and non-PH patients(n = 408)

RHCTrue PAH positive (n = 69)

False PAH positive (n = 129)

YES (n = 198)

No referral to RHCTrue PAH negative (n = 68)False PAH negative (n = 1)

NO (n = 69)

No referral to echoTrue PAH negative (n = 50)False PAH negative (n = 2)

NO (n = 52)

YES (n = 304)

Step 16 non-echo variables

Total risk points > 300?

Missing data(n = 52)

ROC AUC = 0.844(95% CI, 0.795, 0.898)

Step 2Total risk points from Step 1

2 echo variablesTotal risk points > 35?

Missing data(n = 37)

ROC AUC = 0.881(95% CI, 0.824, 0.923)

The DETECT algorithmPPV: 69/198 = 35%

Missed PAH: 3/72 = 4%RHC referral: 198/319 = 62%

DETECT: comparison of two-step algorithm with current guidelines

RHC referral rate

Missed PAH diagnoses

Overall sensitivity

Overall specificity

Overall PPV

Overall NPV

DETECT algorithm

62% 4% 96% 48% 35% 98%

ESC / ERS guidelines*

40% 29% 71% 69% 40% 89%

*Evaluated in 371 DETECT patients with available data for screening variables defined in the guidelines

PPV, positive predictive value; NPV, negative predictive value

DETECT: limitations

Results obtained in a high-risk SSc population– SSc of > 3 years’ duration

– Inclusion criterion DLCO < 60%

– More RHC compared to ESC guidelines (62%-40%)

Cross-sectional design– Frequency of screening cannot be recommended

DETECT: conclusions

The two-step evidence-based DETECT algorithm– Is a sensitive, non-invasive screening tool for detection of

PAH in SSc patients

– Minimizes missed diagnoses

– Identifies PAH earlier in a mildly symptomatic population

– Addresses resource utilization of RHC

The DETECT algorithm has the potential to revise standards of care in SSc patients