Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Ghofrani H-A, Grimminger F, Grünig E, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med 2016; published online April 8. http://dx.doi.org/10.1016/S2213-2600(16)30019-4.

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Supplementary figures and tables

Supplementary Table 1: Frequency of AEs per 100 patient-years in the PATENT-2 study.

AEs, n (rate per 100 patient-years)*

PATENT-1 PATENT-2

Riociguat 2·5 mg–maximum

(n=254) Placebo (n=126) Total (n=396)

Any AE 1185 (2093) 543 (2013) 6065 (591·6)

Five most frequent AEs

at March 2014 cut-off

Nasopharyngitis 29 (51·2) 16 (59·3) 232 (22·6)

Dizziness 46 (81·2) 19 (70·4) 172 (16·8)

Peripheral oedema 52 (91·8) 19 (70·4) 167 (16·3)

Cough 13 (23·0) 14 (51·9) 120 (11·7)

Diarrhoea 43 (75·9) 18 (66·7) 146 (14·2)

AEs of special interest in >5%

of the overall population

Syncope 5 (8·8) 5 (18·5) 60 (5·9)

Hypotension† 27 (47·7) 3 (11·1) 63 (6·2)

Other AEs of interest

Haemoptysis/pulmonary haemorrhage 7 (12·4) 3 (11·1) 56 (5·5)

Median treatment duration in PATENT-2 was 139 weeks (range 0–244 weeks). AE=adverse event.

*Total number of events are shown; a patient may have had more than one event. †Judged by the investigator based on patient symptoms.

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Supplementary Table 2: Results of a Cox proportional-hazards model for association between efficacy

endpoints and survival and clinical worsening-free survival.

Parameter Survival Clinical worsening-free survival

Hazard ratio (95% CI) p-value Hazard ratio (95% CI) p-value

6MWD Baseline

Change from baseline

0·77 (0·67 to 0·89)

0·86 (0·69 to 1·08)

0·0003

0·1908

0·76 (0·69 to 0·84)

0·80 (0·68 to 0·94)

<0·0001

0·0075

NT-proBNP

Baseline

Change from baseline

0·91 (0·87 to 0·96)

0·91 (0·84 to 0·98)

0·0002

0·0134

0·91 (0·88 to 0·94)

0·90 (0·85 to 0·95)

<0·0001

<0·0001

WHO FC Baseline

Change from baseline

0·40 (0·22 to 0·74)

0·61 (0·32 to 1·15)

0·0031

0·1256

0·39 (0·26 to 0·59)

0·55 (0·35 to 0·87)

<0·0001

0·0110

Baseline hazard ratios provide the risk of experiencing a clinical worsening event at any time for a patient with a given baseline, compared with a

patient whose baseline differs by the value of the unit difference for hazard ratio. For each parameter, baseline values and change from baseline

values have been corrected for each other. Unit differences for hazard ratios were 40 m for 6MWD, –300 pg/mL for NT-proBNP, and –1 class for WHO FC. The cut-offs for 6MWD and

WHO FC were based on previously published thresholds;1–3 the cut-off for NT-proBNP was exploratory.

6MWD=6-minute walking distance; CI=confidence interval; NT-proBNP=N-terminal prohormone of brain natriuretic peptide; WHO FC=World Health Organization functional class.

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Supplementary Table 3: Results of a univariate Cox proportional-hazards model for association between

efficacy endpoints at follow-up and survival and clinical worsening-free survival.

Parameter Survival Clinical worsening-free survival

Hazard ratio (95% CI) p-value Hazard ratio (95% CI) p-value

6MWD

Follow-up

0·79 (0·69–0·90)

0·0004

0·77 (0·70–0·84)

<0·0001

NT-proBNP Follow-up

0·91 (0·87–0·96)

0·0002

0.91 (0·88–0·94)

<0·0001

WHO FC Follow-up

0·48 (0·29–0·79)

0·0041

0·45 (0·31–0·64)

<0·0001

Follow-up hazard ratios provide the risk of dying at any time for a patient with a given follow-up value, compared with a patient whose follow-up

value differs by the value of the unit difference for hazard ratio. Unit differences for hazard ratios were 40 m for 6MWD, –300 pg/mL for NT-proBNP, and –1 class for WHO FC. The cut-offs for 6MWD and

WHO FC were based on previously published thresholds;1–3 the cut-off for NT-proBNP was exploratory.

6MWD=6-minute walking distance; CI=confidence interval; NT-proBNP=N-terminal prohormone of brain natriuretic peptide; WHO FC=World Health Organization functional class.

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Supplementary Table 4: Results of a Cox proportional-hazards model for association between efficacy

endpoints and survival and clinical worsening-free survival, including region and PATENT-1 treatment group

as covariates.

Parameter Survival Clinical worsening-free survival

Hazard ratio (95% CI) p-value Hazard ratio (95% CI) p-value

6MWD Baseline

Change from baseline

0·74 (0·64–0·86)

0·83 (0·66–1·05)

<0·0001

0·1170

0·77 (0·69–0·85)

0·81 (0·69–0·96)

<0·0001

0·0143

NT-proBNP Baseline

Change from baseline

0·91 (0·86–0·96)

0·89 (0·82–0·96)

0·0004

0·0050

0·91 (0·88–0·94)

0·90 (0·85–0·95)

<0·0001

0·0003

WHO FC

Baseline

Change from baseline

0·33 (0·17–0·63)

0·54 (0·28–1·07)

0·0008

0·0761

0·38 (0·24–0·59)

0·55 (0·35–0·89)

<0·0001

0·0135

Baseline hazard ratios provide the risk of experiencing a clinical worsening event at any time for a patient with a given baseline, compared with a

patient whose baseline differs by the value of the unit difference for hazard ratio. For each parameter, baseline values and change from baseline

values have been corrected for each other. Unit differences for hazard ratios were 40 m for 6MWD, –300 pg/mL for NT-proBNP, and –1 class for WHO FC. The cut-offs for 6MWD and

WHO FC were based on previously published thresholds;1–3 the cut-off for NT-proBNP was exploratory.

6MWD=6-minute walking distance; CI=confidence interval; NT-proBNP=N-terminal prohormone of brain natriuretic peptide; WHO FC=World Health Organization functional class.

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Supplementary Figure 1: 6MWD in the overall population and treatment-naïve and pretreated subgroups of

PATENT-2. Graph shows mean±SEM. Data are observed values. 6MWD=6-minute walking distance;

SEM=standard error of the mean.

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Supplementary Figure 2: WHO FC in the overall population and treatment-naïve and pretreated subgroups of

PATENT-2. Data are observed values. WHO FC=World Health Organization functional class.

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Supplementary Figure 3: 6MWD in the subgroup of patients from PATENT-2 with idiopathic/familial PAH.

Graph shows mean±SEM. Data are observed values. 6MWD=6-minute walking distance; PAH=pulmonary arterial

hypertension.

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Supplementary Figure 4: WHO FC in the subgroup of patients from PATENT-2 with idiopathic/familial PAH.

PAH=pulmonary arterial hypertension; WHO FC=World Health Organization functional class.

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Supplementary Figure 5: Kaplan–Meier analysis of survival in the population of patients in PATENT-2 with

idiopathic/familial PAH. The estimated survival rate was 98% (95% CI 95–99%) at 1 year and 93% (95% CI 89–

96%) at 2 years. PAH=pulmonary arterial hypertension.

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Supplementary Figure 6: Kaplan–Meier plot showing the effect of WHO FC on survival based on meeting a

predefined threshold of WHO FC I/II at baseline and follow-up. The curve for patients with WHO FC I/II at

baseline and III/IV at follow-up has not been drawn due to the low patient number in this subgroup.

WHO FC=World Health Organization functional class.

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Supplementary Figure 7: Kaplan–Meier analyses showing the effect of 6MWD on clinical worsening-free

survival based on patients being ≥ or < a threshold of: the median value at baseline (380 m; A), median value at

follow-up (419 m; B), and median change from baseline to follow-up (+33 m; C). Differences between groups

were assessed using the log-rank test. 6MWD=6-minute walking distance.

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Supplementary Figure 8: Kaplan–Meier analyses showing the effect of NT-proBNP levels on clinical worsening-

free survival based on patients being ≥ or < a threshold of: the median value at baseline (459 pg/mL; A),

median value at follow-up (267 pg/mL; B), and median change from baseline to follow-up

(–79 pg/mL; C). Differences between groups were assessed using the log-rank test. NT-proBNP=N-terminal

prohormone of brain natriuretic peptide.

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Supplementary Figure 9: Kaplan–Meier analyses showing the effect of WHO FC on clinical worsening-free

survival, based on whether patients were in WHO FC I/II or III/IV at baseline (A) and follow-up (B) and

whether patients’ WHO FC improved or did not improve from baseline to follow-up (C). Differences between

groups were assessed using the log-rank test. WHO FC=World Health Organization functional class.

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