1

A meta-analysis of trials of pulmonary hypertension:

A clinical condition looking for drugs and research methodology

A 63 Y/O woman with idiopathic PH (PAP>50)

Presenting sign:Dyspnea FC III NYHA and lower ext. edema

She want to see is there any therapeutic tool to lead to symptomatic and survival improvement

Pulmonary hypertension (PH) is a

devastating disease characterized

by a sustained elevation of mean

pulmonary artery pressure to >25

mm Hg at rest or >30 mm Hg with

exercise and with a mean wedge

pressure <15 mm Hg.

The disease leads to progressive hypoxemia,right ventricular failure, and death, occurring from a few months to several years after diagnosis.

The median survival of patients with

New York Heart Association (NYHA) functional classes

I to II was 6 years, 2.5 years for NYHA III, and only 6 months for NYHA IV

patients.

Although the pathogenesis of primary PH is unknown,there is consensus that after an endothelial dysfunction/injury, a strong imbalance between antithrombotic/prothrombotic, vasodilatation/vasoconstriction,and

growth inhibition/promitogen forces develops.

Three major pathways are

recognized to play a role in this

imbalance: the

prostacyclin,nitric oxide,and

endothelinpathways,which

involve several mediators.

Early on, endothelial dysfunction results

in a reduced synthesis of endothelium-derived vasodilators(nitric oxide and prostacyclin) along with and overproduction of vasoconstrictors (endothelin-1 and thromboxane), which results in excessive vasoconstriction

Each of these pathwayshas been targeted with 3 different

drug categories,

1.Epoprostenol or other prostacyclin analogues

2.Endothelin receptor antagonists

3.Phosphodiesterase type 5 inhibitors.

These agents has been tested against

placebo or control,providing a consistent

evidence of benefit on the clinical end

points of functional capacity,albeit failing

to support a survival advantage

Methods:

The commonly adopted approach of computer-aided literature search was applied to retrieve from :

EMBASEMEDLINECINAHL databases

All randomized controlled trials published in English from January 1985 to January 2006 addressing the effects of prostacyclin, prostacyclin analogues,endothelin

receptor antagonists, and phosphodiesterase type 5 inhibitors in patients with PH were selected

Sixteen trials have been included.

Each study was used as a unit for

statistical analysis.

The data were analyzed by

intention-to treat

Main outcome measures for the

present analysis were total

mortality, NYHA class

improvement, and exercise

capacity assessed by the 6-minute

walk test (EC6WT).

Hemodynamic effects on pulmonary vascular resistance (PVR), cardiac index, and mean pulmonary artery pressure for individual studies are described but not used in the analysis because of missing values as well as difficulties in extracting data from published articles in a standardized way.

Statistical methods:Treatment effects for total

mortality and NYHA improvement were evaluated as relative risks (RRs) according to the inverse-variance fixed-effect method.

For exercise capacity, we computed the effect size of tested drugs by using the weighted mean difference,

which was calculated after subtracting end-study exercise

endurance (6-min walk distance) from baseline in treated and control groups.

When studies did not directly supply the SE Of the mean for the calculation of effect size,it was estimated from

published data using the methods described by Greenland.

• Alternatively, it was manually obtained from• pictures described as follows: when either the value of the• exercise capacity at the end of follow-up or the SE of the• mean were not reported in the article, they were manually• calculated from pictures (if available). We approached thes

when either the value of the exercise capacity at the end of follow-up or the SE of the mean were not reported in the article, they were manually calculated from pictures (if available)

The Cochran Q test was used to assess the magnitude of effect size heterogeneity. When the heterogeneity test reached

the formal level for statistical significance to assess heterogeneity (P<.10), the null hypothesis of homogeneity of the treatment effects across the studies was rejected and

the analysis repeated by calculating a random-effect model

To examine the strength of the association between treatment effects on total mortality and the end-study change of exercise capacity,we fitted a univariate

inverse variance– weighted linear regression with RR of total mortality as a dependent variable

To assess the association between baseline exercise capacity and probability of death in the population of patients recruited in the various

studies, we fitted both linear and polynomial linear regressions with death and baseline walking distance in the control group as dependent and explanatory variables,

The regression models were weighted according to the dimension of the control group results from all methods are reported along with their 95% CIs. All analyses were done using the SAS statistical package

Results:Characteristics of studies

Table I presents a synoptic view of the 16 randomized clinical trials recruiting >1900 patients with PH that have been published over a 15-year period (1990-2005)

1038 Macchia et al

American Heart Journal

June 2007

Table I. Baseline characteristics of trials

Active Etiology of

Acronym N Intervention Placebo FUP PH (%) NYHA III (%) NYHA IV (%)

Rubin et al25 CIPPPH 23 E No 2 m

IPAH

(100) 65 26

Barst et al26 PPHSG 81 E No 12 w

IPAH

(100) 74 26

Badesch et al27 PHSSDSG 111 E No 12 w

APAH

(100) 78 17

Olschewski et al28 AIR 203 I Yes 12 w IPAH (50) 59 41

APAH

(22)

Galie` et al29

TED (28)

ALPHABET 130 B Yes 12 w IPAH (48) 51 0

Simmoneau et al30

APAH

(52)

TSG 470 T Yes 12 w IPAH (58) 81 7

Barst et al31

APAH

(42)

BSG 116 B Yes 9 m IPAH (74) 47 0

Channick et al32

APAH

(26)

BPH 32 Bo Yes 12 w IPAH (84) 100 0

Rubin et al33

APAH

(16)BREATHE-

1 213 Bo 125 Yes 16 w IPAH (70) 92 8

Barst et al34

Bo 250

APAH

(30)

STRIDE-1 178 SX 100 Yes 12 w IPAH (53) 66 1

Humbert et al35

SX 300

APAH

(47)BREATHE-

2 33 E + Bo Yes 16 w IPAH (82) 76 24

Ghofrani et al36

E

APAH

(18)

S&ISPH 30 S 12.5 No 0 IPAH (33) 100

S 50

APAH

(20)

S 12.5 + I TED (43)

Ghofrani et al37

S 50 + I Other (3)

SLFPH 16 S 50 No 0APAH (25) 62 38

Sastry et al38

E Other (75)

SPPH 22 S Yes 12 wIPAH (100) 18 0

Galie et al39 SUPER-1 278 S 20 Yes 12 w IPAH (63) 58 3

S 40

APAH

(30)

Wilkins et al40

S 80 Other (6)

SERAPH 26 S 150 No 16 w IPAH (88) 100 0

Bo 125

APAH

(12)

1038 Macchia et al

American Heart Journal

June 2007

Table I. Baseline characteristics of trials

Active Etiology ofAcronym N Intervention Placebo FUP PH (%) NYHA III (%) NYHA IV (%)

Rubin et al25 CIPPPH 23 E No 2 m IPAH (100) 65 26Barst et al26 PPHSG 81 E No 12 w IPAH (100) 74 26

Badesch et al27 PHSSDSG 111 E No 12 wAPAH (100) 78 17

Olschewski et al28 AIR 203 I Yes 12 w IPAH (50) 59 41APAH (22)

Galie` et al29

TED (28)ALPHABE

T 130 B Yes 12 w IPAH (48) 51 0

Simmoneau et al30

APAH (52)TSG 470 T Yes 12 w IPAH (58) 81 7

Barst et al31

APAH (42)BSG 116 B Yes 9 m IPAH (74) 47 0

Channick et al32

APAH (26)BPH 32 Bo Yes 12 w IPAH (84) 100 0

Rubin et al33

APAH (16)BREATHE

-1 213 Bo 125 Yes 16 w IPAH (70) 92 8

Barst et al34

Bo 250 APAH (30)STRIDE-1 178 SX 100 Yes 12 w IPAH (53) 66 1

Humbert et al35

SX 300 APAH (47)BREATHE

-2 33 E + Bo Yes 16 w IPAH (82) 76 24

Ghofrani et al36

E APAH (18)S&ISPH 30 S 12.5 No 0 IPAH (33) 100

S 50 APAH (20)S 12.5 + I TED (43)

Ghofrani et al37

S 50 + I Other (3)SLFPH 16 S 50 No 0 APAH (25) 62 38

Sastry et al38

E Other (75)SPPH 22 S Yes 12 w IPAH (100) 18 0

Galie et al39 SUPER-1 278 S 20 Yes 12 w IPAH (63) 58 3S 40 APAH (30)

Wilkins et al40

S 80 Other (6)SERAPH 26 S 150 No 16 w IPAH (88) 100 0

Bo 125 APAH (12)

American Heart Journal

Macchia et al 1039Volume 153,

Number 6

Table I (continued)

DyspneaATT (%) VD (%) DX (%) DIU (%) Primary outcome measure HD Survival Quality of life

assessment

100 43 17 56 EC6WT Yes97 63 NR NR EC6WT Yes Yes Yes Yes85 68 NR NR EC6WT Yes Yes No YesNR 54 NR NR NYHA/EC6WT Yes Yes Yes Yes73 NR 19 53 EC6WT Yes Yes No YesNR NR NR NR EC6WT Yes Yes Yes Yes

NR NR NR NRDeath/transplantation/

rescue therapy/ Yes - Yes YesN25% decreased Po2

72 47 NR NR EC6WT Yes No No Yes71 47 NR 52 EC6WT No No No Yes

80 47 38 65 Change Pv¯o2 Yes No Yes Yes88 27 27 88 Total pulmonary resistance Yes No No YesNR NR NR NR Hemodynamic No No No

NR NR NR NRPulmonary vascular

resistence index Yes No No NoNR NR NR NR Exercise time test Yes No Yes NoNR NR NR NR EC6WT Yes Yes No Yes92 23 54 62 Right ventriclular mass Yes No No Yes

58% Epoprostenol or other prostacycline analogues

23% Endothelin receptor antagonists,

19% Phosphodiesterase type 5 inhibitors, respectively.

The most frequently used

efficacy end point was

exercise capacity, assessed

using the EC6WT.

Clinical severity of the study populations:

Nearly 65% of patients had a sporadic form of primary PH, whereas 30% had PH associated with other conditions (particularly collagen vascular disease).

As to disease severity, the proportion of patients in NYHA/World Health Organization (WHO) dyspnea classes III and IV was around 70% and 11%, respectively.

The overall mortality of 3.2% (62 of the 1892 patients)was closely related to the baseline exercise capacity

Curvilinear relatioship shown in Figure 1, which documents a progressively worsening prognosis of up to 20% for patients with low

exercise capacity (<330 m) and an almost stable risk of death (about 5%) for patients with more preserved functional activity.

Effects of experimental treatments

Mortality:

The cumulative RR estimate of death was

a statistically nonsignificant reduction of 30% (95% CI 0.41-1.22, P=.208) in the active treatment groups as compared with control groups

With respect to the effects of prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, no statistically significant between group heterogeneity emerged in subgroup analyses in total mortality or between the subgroups testing each of the treatments.

As compared with studies recruiting

patients with higher exercise

capacity (>330 m), those enrolling

subjects with worse physical

performance had definitely higher

mortality rates (46/913, 5.0% vs

13/946, 1.4%).

However, the proportional effect of tested treatments on mortality (RR) was 0.63 (95% CI 0.20-1.87, P=.43)

versus severely impaired exercise capacity of 0.69 (95% CI 0.38-1.80,

P=.25, between-group heterogeneity test

P=.903)

The absence of a relationship between

baseline

exercise capacity and/or its changes

during follow-up and treatment benefits

on mortality was confirmed by the

results of the inverse variance–weighted

linear regression with RR of total

mortality as a dependent variable

Exercise capacity: Experimental treatments significantly improved exercise capacity as assessed by the EC6WT.

The weighted mean improvement of exercise capacity in patients allocated to experimental treatments was

42.8 m(95% CI 27.8-57.8, P<.001)

however, did not show heterogeneity of benefit between studies testing the 3 different drug categories (P=.672). Accordingly, the within-group heterogeneity test result for studies testing prostacyclin analogues was statistically significant (P<.001)

As compared with studies recruiting patients with less severe exercise capacity impairment at baseline, those including patients with more severe exercise

capacity had a slightly higher, nonsignificant improvement in end-study exercise capacity (46.6 vs 38.6 m)

Dyspnea status:

As for trials reporting NYHA or WHO dyspnea status,experimental treatments(RR [95% CI]) significantly improved dyspnea status by

at least one functional class (RR 1.83,

95% CI 1.26-2.66, P<.001)

The pooled analysis showed that

33% (210/637) and 14.7% (69/469) of patients allocated to experimental and control treatments, respectively,had a significant symptomatic improvement.

Tested treatments were more effective in studies enrolling patients with more versus less pronounced impairment of exercise capacity at baseline (relative probability of improving functional class 4.64, 95% CI

1.52-1414, P = .002 vs 1.48, 95% CI 1.10-1.99, P =.010)

Other outcome measures:

A relatively wide range

of baseline values of PVR were observed at baseline in the various studies.

The impact of treatments on PVR was usually statistically significant, the improvement in mean values ranging from 12% to 36%

Mean baseline pulmonary artery pressure varied approximately between 50 and 60 mm Hg.

Pharmacologic interventions determined in most cases a statistically significant reduction in end-study mean pressure, ranging from nearly 2% to 25%.

Discussion:Unambiguous major advances have been

developed over the last years in the field of PH.

New insights into the molecular mechanisms and genetic background contributed to the design and further test of several pharmacologic agents aimed at improving survival and quality of life of patients with PH

However, the cumulative benefits of these interventions on relevant clinical outcomes—particularly overall mortality—had not been reported.

This meta-analysis provides 4 main results

(1) new agents were not associated with a statistically significant survival benefit among patients with PH;

(2) No relationshipwas found between changes in exercise capacity and effect on survival;

(3) treatments significantly

improved dyspnea, exercise tolerance, and hemodynamic parameters

(4) populations and methodology

adopted in clinical trials were extremely homogeneous.

Clinical research was focused on severely ill patients with PH.

Nearly 80% of patients included in the trials

had NYHA/WHO dyspnea class III/IV, with half of the patients walking <330 m at the baseline 6-minute walk test.

The main clinical priorities for this population were the demonstration of symptomatic improvement and were well tackled by clinical trials.

In these populations, clinical trial successfully demonstrated that all new treatments significantly improved

exercise capacity and symptoms.

On the other hand, less symptomatic patients (NYHA/WHO class II-III and with a baseline exercise capacity>330 m) were less represented in the trials.

In this population, median survival is 2.5 years for those in NYHA III and 6 years for those in NYHA II.

For this reason, the main objective for this population should not be only exercise capacity and quality of life but overall

survival and avoidance of clinical worsening as well as long-term safety concerns.

Despite clinical research being focused on a severely ill population, our analysis revealed a statistically nonsignificant 30% reduction in mortality in patients receiving experimental treatments

For severely ill patients, it is clear that a medication that improves function but does not prolong life might still be considered useful as long as it does not shorten survival.

However, our findings should promote a

reconsideration on the expectations that patients, physicians, and the health system currently have of these agents.

To claim repeatedly that mortality reduction

is already achieved and that it is not ethical to settle on mortality as an end point is incoherent with both results and current agenda

Furthermore, although the statistically significant benefit on exercise capacity

shown in individual trials has been confirmed, no correlation has been found between this surrogate end point and mortality.

This negative finding is particularly worrying because one of the main reasons supporting the registration of the indication for each of the new and highly expensive(nearly $100000 for parenteral prostacyclin, $80000 for bosentan and inhaled iloprost, and from $12000 to

$50000 for sildenafil per year, depending on the dose used) treatments was the predictive value of the surrogate measure on clinical outcomes.

Our analysis confirms that baseline exercise capacity is closely related to survival in patients with PH;

however, this does not necessarily mean that changes in the distance walked could be used as a surrogate

for mortality.

This is not surprising, and medical

literature offers several examples of mismatches between physiologic intuition and clinical outcomes.

This is the case with ejection fraction and heart failure or ventricular arrhythmias and arrhythmic death.

Results show that new treatments significantly improved exercise capacity with no heterogeneity in achieving this effect.

In addition, prostacyclin and analogues as well as endothelin receptor antagonists

improved symptoms.

This is important for the single severely symptomatic patient; however, it should be also underlined that the symptomatic improvement documented over such a short-term period can hardly be assumed as a completely satisfactory therapeutic tool to be used over a long-term period

New treatments moderately but significantly improve hemodynamic parameters.

However, the clinical implications of these modification are less evident.

The insufficient methodological quality of study designs (specifically with respect to sample size and/or duration of the follow-up) is often justified with the fact that PH is a rare disease.

The public health implications of registering drugs with an unclear evidence-based benefit profile (while imposing major economic burdens) require a substantial modification of approach.

• Tadalafil: A Long-Acting Phosphodiesterase-5 Inhibitor for the Treatment of Pulmonary Arterial Hypertension

In a controlled clinical study in patients with PAH, patients receivingtadalafil in a total daily dose of 40 mg had significant improvements in their 6- minute walk distance (33 mfrom baseline) and time to clinical worsening compared with those receiving placebo (both, P < 0.05).