Beneficial effects of angiotensin-converting enzyme inhibitor and nitrate association on left ventricular remodeling in patients with large acute myocardial infarction: the delapril remodeling after acute myocardial infarction (DRAMI) trial

Article Outline

• Abstract
• Methods
  • Echocardiographic evaluation
  • Study end points
  • Statistical analysis
• Results
  • Echocardiography
  • Clinical events
  • Tolerability and compliance
• Discussion
• Appendix. 
• References
• Copyright

Abstract 

Background

In the large-scale trial, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-3 (GISSI-3), patients receiving the combination of lisinopril and glyceryl trinitrate benefited most from experimental therapy. Therefore, a multicenter, randomized, double-blind study, Delapril Remodeling After Acute Myocardial Infarction (DRAMI), was designed to assess (1) the possible additive beneficial effect on left ventricular remodeling of nitrates when combined with an angiotensin-converting enzyme inhibitor (ACEI), and (2) the tolerability of a new ACEI, delapril, in respect to lisinopril in patients with large myocardial infarction (MI).

Methods

A total of 177 patients were randomized to receive delapril plus isosorbide-5-mononitrate (IS5MN) placebo, delapril plus IS5MN, lisinopril plus IS5MN placebo, or lisinopril plus IS5MN starting within the first 36 hours after the onset of symptoms and continuing for 3 months.

Results

More than 80% of the patients showed extensive ST-segment changes and 36.7% had signs or symptoms of heart failure during the first 36 hours. Over 3 months, IS5MN reduced, by 76%, the increase in LVEDV (17.4 ± 5.0 mL placebo vs 4.2 ± 4.4 mL IS5MN, P = .0439), reversed the increase in LVESV (7.5 ± 3.9 mL placebo vs −5.5 ± 2.9 mL IS5MN, P = .0052), and increased the recovery of LVEF (1.9% ± 1.3% placebo vs 6.7% ± 1.2% IS5MN, P = .0119). Overall, 3-month mortality was 10.2%; the most frequent clinical events were new episodes of severe heart failure (18.1%), persistent hypotension (10.7%), and post-MI angina (18.1%), with no differences between treatment groups.

Conclusions

Administration for 3 months of IS5MN combined with an ACEI, both started within 36 hours from the onset of symptoms, was safe and effective in reducing LV dilation and dysfunction after MI. The 2 ACEIs, delapril and lisinopril, appeared to be equally well tolerated.

A 1-month treatment with an angiotensin-converting enzyme inhibitor (ACEI) after myocardial infarction (MI), started within the first 36 hours after the onset of symptoms, saves 5 lives out of 1000 treated patients.1 The reduction in mortality appears to be higher in more severely ill patients, such as those with signs or symptoms of left ventricular (LV) dysfunction2 or with anterior MI.1 Although nitrates have been shown in animals and in humans to reduce LV remodeling after MI and to improve LV function,3, 4, 5 their systematic administration for at least 1 month after MI proved to be ineffective in reducing morbidity and mortality in 2 large-scale clinical trials, the Fourth International Study of Infarct Survival (ISIS-4)6 and Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-3 (GISSI-3).7 Similarly, another nitric oxide (NO) donor, molsidomine, proved ineffective when started within the first 24 hours from the onset of symptoms of MI and continued for 12 days.8

However, a per-protocol analysis of GISSI-37, 9 showed that the group that benefited most from experimental therapy was the one assigned lisinopril and glyceryl trinitrate, in which a more favorable outcome was shown for the primary outcome of mortality and for the combined end point of mortality and severe left ventricular dysfunction.

These findings might derive either from a beneficial effect of long-term nitrates per se on LV remodeling after MI5 or from a drug-to-drug interaction with an ACEI.10 Evidence of additional benefits of nitrates combined with an ACEI has been reported in normal volunteers,11 patients with chronic ischemic heart disease,12 and congestive heart failure.13 Therefore, it was of interest to determine whether a nitrate derivative, isosorbide-5-mononitrate (IS5MN), could confer additional benefit to an ACEI on LV remodeling after MI. In order to increase, in respect to GISSI-3, the chances of finding an effect of nitrates on LV remodeling, only patients with large MI (extensive electrocardiographic (ECG) changes and/or signs or symptoms of LV dysfunction) were selected for the present study: Delapril Remodeling After Acute Myocardial Infarction (DRAMI). The DRAMI trial differed from the GISSI-3 trial in that DRAMI was double blinded and used central reading of variables measured in 2-dimensional echocardiograms.

A secondary aim of the DRAMI trial was to compare the safety profile in the acute setting of MI of a new highly-lipophilic, non-sulphydril ACEI, delapril,14 with that of the well-known lisinopril.7

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Methods 

DRAMI was a randomized, double-blind trial that enrolled 177 patients with MI from 18 Italian centers (Appendix). Patients aged >18 years who had experienced an MI within 36 hours were considered eligible if at least 1 of the following conditions was fulfilled: (1) ≥1 mm ST-segment elevation in at least 7 leads of a 14 lead (12 standard + 2 right) surface ECG, (2) Killip class 2 or 3 at entry, and (3) signs or symptoms of left ventricular dysfunction within the first 36 hours.

Exclusion criteria were relative contraindications to ACEI use, serum creatinine >2mg/dL (177 μmol/L), Killip class 4, and systolic blood pressure (SBP) ≤100 mm Hg not increasing by 36 hours after the onset of pain. Inadequate echogenicity and refusal to sign informed consent were other reasons for exclusion. Recommended treatments were thrombolytics, aspirin, and intravenous β-blockers, to be given as soon as possible in the absence of contraindications. Intravenous glyceryl trinitrate was allowed only for a specific indication such as persistent chest pain, high blood pressure, or cardiac failure. Before randomization, a surface ECG, an echocardiogram, blood pressure, and a blood sample for blood chemistry were obtained in all patients. ECG and echo were repeated at predischarge and 3 months. Blood pressure was monitored over the first 2 days every 3 hours and again with the same frequency on day 10.

Study treatments were randomly assigned centrally, after checking for inclusion/exclusion criteria by fax; each of the 4 treatments (delapril plus nitrate, delapril plus nitrate placebo, lisinopril plus nitrate, lisinopril plus nitrate placebo) had the same probability of being assigned. Delapril and lisinopril formulations, and IS5MN and its placebo were made indistinguishable.

Initial doses of ACEI for the first 2 days were, for delapril, 7.5 mg twice daily, and for lisinopril, 5 mg in the morning and its placebo in the evening.

In the absence of symptomatic hypotension or SBP <100 mm Hg, the doses were doubled for both drugs during days 3 through 7; maintenance doses were 30 mg of delapril or 10 mg of lisinopril once daily.

Controlled release oral isosorbide-5-mononitrate (IS5MN), 50 mg, or its placebo was given once a day. ACEI and IS5MN were started simultaneously within 36 hours from onset of symptoms and continued for 3 months.

Whenever deemed necessary by the attending physician, doses of the ACEI were halved (rescue treatment) or the treatment was temporarily stopped. Compliance was predefined as assumption of at least 75% of the treatment by protocol.

Echocardiographic evaluation 

An echocardiographic core lab was established (Mario Negri Institute, Milano, Italy) where all echocardiograms were to be read, in order to minimize between-reader variability. Before the trial, echocardiographers from each participating center underwent training and submitted an echocardiogram to ensure adherence to echocardiographic protocol. Images were recorded on 0.5 inch VHS 0.5 videotapes to allow real time and slow motion playback review and a consecutive digitalization of single frames. In each patient, the following views were to be recorded: parasternal long-axis, parasternal short-axis (obtained at mitral valve level and at mid-papillary level), and apical 4-, 5-, and 2-chambers, following the recommendations of the American Society of Echocardiography.15 A technically acceptable 2-dimensional echocardiogram included a minimum of 3 of these 6 possible views with adequate endocardial definition. Pulsed Doppler of transmitral inflow from the apex was recorded at 50 mm/s at the point of maximal velocity of E wave. Frames of the LV were digitized and analyzed off-line by an ad hoc software (Andreoni G, Capello P, Livraghi F, Echocertifier 1.0 Manual, 1997).

Patients undergoing coronary revascularization, which was not a study end point, were followed up to study end: 3 months. However, due to the expected improvement of LV dimensions and function after coronary revascularization, it was recommended to perform an echocardiogram right before the revascularization procedure, and this study was used in the analysis as final echocardiographic evaluation.

Images were selected for end-diastolic (apex of R wave or biggest visible cavity) and end-systolic (preceding initial early diastolic mitral opening or smallest LV-chamber dimension) measurements. For all measurements, 3 separate cardiac cycles were traced.

Major echocardiographic end points were (1) LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) (modified Simpson’s rule technique from apical 4-chamber view), (2) LV ejection fraction (LVEF), and (3) E/A ratio (from the pulsed-wave Doppler flow velocities of mitral inflow).

The extent of asynergy of the LV wall was assessed by visual determination of akinetic and dyskinetic segments based on an 11-segment model according to Edwards et al.16

Study end points 

The primary aim of this study was to measure, by echocardiography, a reduction by IS5MN of 50% in the LVEDV increase over 3 months when comparing ACEI plus IS5MN with ACEI plus IS5MN placebo. Power calculations indicated that 122 patients per group were necessary to show the above difference with an α error of 0.05 and a β error of 0.15.

The incidence of main clinical events was computed individually and in combination. During the 92-day follow-up, a patient reached the combined end point if she/he died, or had one of the following: reinfarction, severe heart failure (NYHA class III-IV or cardiogenic shock), LVEF ≤35%, persistent hypotension (SBP <90 mm Hg for at least 1 hour), or severe renal dysfunction (requiring dialysis).

Although the study was not sized to evaluate equivalence between 2 ACEIs, the incidence of the combined end point in the lisinopril and delapril groups was also compared.

Statistical analysis 

The primary analysis was done on echocardiographic variables, by comparing IS5MN to its placebo according to the intention-to-treat principle and by treatment. Analysis by treatment excluded all patients predefined as noncompliant by the study protocol (ie, compliance with study drugs <75%).

All data were centrally processed and analyzed blinded to drug treatment by the Data Coordinating Center (Mario Negri Institute). LV volumes were not normalized by body surface area because within-patient changes were analyzed.

Continuous variables were analyzed by the Student’s t test or Wilcoxon test when appropriate. Analysis of variance was performed on the changes in echocardiographic variables at 3 months versus baseline.

The χ² test or Fisher’s exact test was used to analyze categorical variables.

All tests of significance were 2-tailed, and a value of P < .05 was considered statistically significant. All statistical analyses were performed with the SAS software system version 8.0 (SAS Institute, Cary, NC). Numerical data are reported in the text as mean ± standard error of the mean (SEM), whenever appropriate.

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Results 

Between February 1997 and February 1999, 177 patients were enrolled in the trial by 18 participating coronary care units. At randomization, 82.5% of patients had ≥7 leads with ≥1 mm ST-segment elevation, and 36.7% had clinical evidence of heart failure; 56.0% of the patients were considered eligible for the presence of both criteria. Creative kinase (CK) at randomization was 1136 ± 1431 IU/L, CK max was 3013 ± 2069 IU/L. According to protocol recommendations, 81.4% of the patients had thrombolysis, 43.5% received intravenous β-blockers, and 91.5% received aspirin. Glyceryl trinitrate was infused intravenously during the first 24 hours for specific indication in 87.0% of the patients. The treatment groups at baseline were comparable for all variables (Table I). After symptom onset, but before randomization, atrioventricular block was reported in 5.6% of patients, and sustained ventricular tachycardia or ventricular fibrillation in 7.3% of patients. SBP was ≤120 mm Hg in 52.6% of patients, and heart rate (HR) was >100 beats per minute in 8.5% of patients at entry.

Table I. Baseline characteristics of the patients (n = 177)

i.v. Intravenous; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Echocardiography 

An echocardiogram that could be quantitatively analyzed was obtained in 91.5% of the patients (162/177) at randomization, in 89.0% (145/163) at predischarge, and in 76.1% (121/159) at 92 days (end of the study). Overall 20 out of 471 (4.2%) echocardiograms received by the core laboratory were discarded because of insufficient quality. A total of 88 patients were compliant and had complete echocardiographic data up to 3 months and were included in the analysis by treatment. Main baseline echocardiographic variables were similar in all treatment groups. The LVEF was slightly depressed, averaging 44.9% ± 11.5% (Table II).

Table II. Main echocardiographic variables at randomization by study treatments (mean ± SD)

Values presented as mean ± SD. A/D score, a/dyskinetic score; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction.

Akinetic/dyskinetic score decreased from baseline to study end, from 25.8% ± 1.1% to 15.8% ± 1.2% (P < .001), in a similar manner in all groups.

In the by-treatment analysis on 88 patients overall, LV remodeling appeared to be unaffected by IS5MN at prediscahrge. However, IS5MN significantly attenuated LV dilation over 92 days: it reduced by 76% the increase in LVEDV (17.4 ± 5.0 mL placebo vs 4.2 ± 4.4 mL IS5MN, P = .0439) and reversed the increase in LVESV (7.5 ± 3.9 mL placebo vs −5.5 ± 2.9 mL IS5MN, P = .0052). Similarly, IS5MN increased the recovery of LVEF (1.9% ± 1.3% placebo vs 6.7% ± 1.2% IS5MN, P = .0119). E/A ratio increase in placebo patients tended to be attenuated by IS5MN, but the effect was not statistically significant (P = .5421) (Figure 1).

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• Figure 1. 

  Changes from randomization to end of study (92 days) in LVEDV, LVESV, LVEF and E/A for IS5MN and its placebo. Per-protocol analysis. IS5MN (solid bars), IS5MN placebo (open bars). Mean ± SEM.

The effect of IS5MN showed the same trend for all variables when echocardiographic data were analyzed by intention-to-treat in 118 patients overall, even if for LVEF the effect of IS5MN did not reach statistical significance. In detail, IS5MN reduced, by 66%, the increase in LVEDV (14.8 ± 4.0 mL placebo vs 4.0 ± 3.9 mL IS5MN, P = .0436) and reversed the increase in LVESV (5.6 ± 3.2 mL placebo vs −3.2 ± 2.9 mL IS5MN, P = .0241). IS5MN tended to increase the recovery of LVEF (2.8% ± 1.3% placebo vs 5.5% ± 1.2% IS5MN, P = .0724).

No difference was found in echocardiographic variables between the lisinopril and delapril groups.

Clinical events 

Out of the 18 (10.2%) patients who died during the study, 14 (7.9%) died inhospital, without differences between treatment groups (Table III). The 92-day incidence of other clinical events by IS5MN and by ACEI group did not show differences. Accordingly, the incidence of the combined end point for tolerability was similar among groups (Table III). The 4 cases of renal failure did not require dialysis, but were considered by the responsible clinician as severe: serum creatinine ranged from 221 to 371 μmol/L and blood urea nitrogen ranged from 131 to 159 mg/100 mL.

Table III. 92-Day incidence of clinical events by treatment in the 177 patients enrolled to DRAMI

Values presented as number of patients (%)

The difference in frequency of episodes of persistent hypotension reported (mostly in the first 3 days after MI, 57.9%) for the 2 ACEIs did not reach statistical significance (P = .3916). No excess of persistent hypotension was found with IS5MN.

SBP, diastolic blood pressure (DBP), and serum creatinine mean values at baseline, discharge, and at study end are reported in Table IV by ACEI group. There were no differences between delapril and lisinopril, nor between IS5MN and its placebo (data not shown).

Table IV. Systolic and diastolic blood pressure and serum creatinine by ACEi

Values presented as mean ± SD. Cr, Creatinine.

SBP time course during the first 48 hours showed a decrease of about 10 mm Hg within the first 6 hours, then SBP was slightly lower in the lisinopril group than in the delapril group; but these differences were not statistically significant at any time point (Figure 2, A). These slight differences disappeared when blood pressure was monitored on day 10. SBP time course was not affected by IS5MN, neither during the first 48 hours (Figure 2, B) nor on day 10.

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• Figure 2. 

  Systolic blood pressure (SBP) time course in delapril (n = 85, open squares) and lisinopril (n = 91, solid diamonds) groups (A) and in IS5MN (n = 86, solid circles) and IS5MN placebo groups (n = 90, open triangles) (B) during the first 48 hours after randomization. Mean ± SEM.

Overall, 4 patients underwent percutaneous coronary angiography (PTCA) before randomization, and 38 patients during follow-up: 21 PTCA and 17 coronary artery bypass graft (CABG). There were no differences in the incidence of revascularization between treatment groups.

Tolerability and compliance 

IS5MN or its placebo were administered according to the study protocol or temporarily suspended (median duration of suspension: 2 days [1-21 days]) in 155 of 173 patients (89.6%): 80 of 88 patients (90.9%) in the placebo group, and 75 of 85 (88.2%) patients in the IS5MN group. Data on compliance were missing in 4 patients.

Lisinopril or delapril were administered according to study protocol or temporarily suspended (median duration of suspension: 2 days [1-9 days]) in 160 of 173 patients (92.5%): 80 of 83 (96.4%) in the lisinopril group, and 80 of 90 (88.9%) in the delapril group. A total of 136 of 173 (78.6%) patients were compliant to both study treatments.

The reasons for permanent discontinuation of IS5MN or its placebo in 18 patients were headache in 6, CABG/PTCA in 5, patient refusal in 4, and other reasons in 3.

The reasons for permanent discontinuation of lisinopril or delapril in 13 patients were CABG/PTCA in 6, cough in 1, patient refusal in 3, and other reasons in 3. No statistically significant differences were observed between study groups.

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Discussion 

ACEIs are part of the recommended therapy of MI because they reduce mortality and the incidence of LV dysfunction and reinfarction.1, 2 In contrast, the systematic administration of nitrates, although supported by experimental3 and small-size clinical studies,4, 5 proved to be ineffective in reducing mortality in 2 large-scale trials, ISIS-46 and GISSI-3.7 However, exploratory analyses of the GISSI-3 database showed a statistically significant lower incidence of the combined end point of mortality and severe LV dysfunction in the group receiving both lisinopril and glyceryl trinitrate.

The DRAMI study was designed to verify the hypothesis that the systematic combination of a nitrate with an ACEI, started early after MI in patients of intermediate risk and continued for 3 months, would produce additional reduction of LV remodeling—a reduction already shown by ACEI alone.18, 19 Indeed, the results of DRAMI show that in this context, IS5MN reduces LV dilation and improves the recovery of LVEF when combined with an ACEI. The coherence between intention-to-treat and by-treatment analyses support these findings, even if the number of patients included in the analysis was smaller than planned. This beneficial effect on LV remodeling post-MI occurred in the absence of undesired effects on blood pressure and on clinical events. Although the number of patients enrolled does not allow firm conclusions on the incidence of events to be drawn, this was not a study end point.

The effect was apparent notwithstanding the large use of intravenous glyceryl trinitrate (87.0%) in the first 24 hours in both groups for specific clinical indications. This suggests that the major determinant of the observed benefit might not be the nitrate within the first 2 to 3 days after MI, but its systematic coadministration with the ACEI during the following 3 months. In fact, the effect of IS5MN on LV remodeling was evident only at 92 days, while no significant differences could be shown at predischarge, (ie, at a median of 11 days after index MI). Although it has been previously shown that glyceryl trinitrate reduced/prevented LV remodeling after MI in animals and humans,3, 4 probably through a very early unloading of LV, the present study neither proves nor disproves this early effect because most of the patients were receiving open-label glyceryl trinitrate infusion. The results of the present study appear to be consistent and to expand those of the multicenter trial assessing the effects of 6-month intermitent (12 hours on and off) glyceryl trinitrate patch therapy started within 7 days from the index event in patients surviving Q-wave MI.5 This trial showed that patches delivering 0.4 mg/h of glyceryl trinitrate significantly reduced LV dilation and improved LVEF from an average baseline value of 45%, similar to that found in DRAMI. In the same trial, patients also receiving open-label ACEI in the glyceryl trinitrate group failed to show significant differences from the placebo group, probably due to the small size of this subgroup (about 60 patients overall) and to the very small LV dilation found in the placebo group. The benefit of long-term transdermal glyceryl trinitrate on LV remodeling was more marked in patients with baseline LVEF ≤40%, but this last finding was not confirmed by a similar post-hoc analysis on our data, possibly due to the inadequate size of the subgroup.

Only one published study formally tested the effect of nitrates versus placebo on LV remodeling in patients treated with ACEIs, but this was done in the setting of congestive heart failure.13 Similar to what was observed in DRAMI, in this heart failure study the addition of a high daily dose (50-100 mg) of transdermal glyceryl trinitrate to ACEI over 3 months decreased LV dilation and improved LV function more than placebo.

As observed in GISSI-3, akinetic/dyskinetic echocardiographic score gradually decreased and LVEF increased over time after MI in the overall population.20 In DRAMI, the decrease in akinetic/dyskinetic score over 92 days appeared to be unaffected by study treatments; the recovery of LVEF was improved by IS5MN, compared to its placebo.

Patients enrolled in the DRAMI study were at somewhat higher risk than those of GISSI-3, but at lower risk than those in trials in which ACEIs were started later after MI.2 Three-month mortality in DRAMI was 10%, compared with 9.1% 6-month mortality in GISSI-39 (lisinopril group). To adequately compare mortality in the 2 trials, it should be considered that patients were enrolled to DRAMI after an average of 22.2 hours, while the average was 10.7 hours for GISSI-3. This by itself would decrease mortality by not including the relevant fraction of very early deaths. Moreover, 36.7% of the patients in DRAMI and 14.1% in GISSI-3 had evidence of LV dysfunction at entry, and 21.5% of the patients in DRAMI and 8.7% in GISSI-3 developed new episodes of LV dysfunction during follow-up.

The careful up-titration of the dose of ACEI, based on previous experience, lead to a 10.7% overall incidence of persistent hypotension, similar to that observed in GISSI-3 and in a systematic overview on almost 100,000 MI patients.1 The incidence of individual clinical events and of the combined end point was slightly higher with delapril than with lisinopril, but never statistically significant. The slight unbalance might be attributed to the much more limited clinical experience in the acute setting of MI with delapril than with lisinopril, which had been successfully titrated in 19,000 patients with MI enrolled in GISSI-3. Nevertheless, blood pressure profiles in the first 48 hours after MI did not show any difference between lisinopril and delapril, and resembled those already reported for lisinopril in the GISSI-3 Pilot study.21 In agreement with a well accepted class effect, the effects of lisinopril and delapril on echocardiographic variables did not differ. Overall, these observations should be viewed with caution, because the study was not sized to assess equivalence between the 2 ACEIs.

The most likely mechanisms of the beneficial effects of IS5MN are the nitrate class actions,22 such as preload and afterload decrease, improvement of myocardial perfusion, and decrease in endothelial dysfunction, which would add to the effects of an ACEI.11 Indeed, in a similar context, the relevance of a pure pharmacological effect of a nitrate derivative has been shown by Mahmarian et al5: after 1-week withdrawal of glyceryl trinitrate, its favorable effects on LV volume disappeared.

Moreover, ACEIs might have enhanced the above-mentioned effects of IS5MN and/or decreased tolerance by 2 possible mechanisms: (1) inhibition of the increased production of superoxide, one of the causes of nitrate tolerance, by decreasing angiotensin II,²³ and/or (2) increase in endogenous NO by ACEI, through the inhibition of bradykinin degradation.10 In any case, the present study was not designed to give mechanistic insights.

In conclusion, the systematic use of an organic nitrate, started within the first day from the onset of symptoms of MI, together with an ACEI improves the recovery of LV function after MI. It is possible that this beneficial effect can be better shown in patients with anterior infarction and/or some degree of LV dysfunction. An adequately powered large-scale trial and a properly performed post-hoc overview of existing trials are needed to verify whether improvement in LV structure and function by nitrates combined with an ACEI confer a clinical advantage.

The large use of recommended treatments, thrombolysis, β-blockers, aspirin, and the relatively high number of revascularization procedures performed during the trial, suggest that the study was done in an up-to-date clinical setting and support the applicability of the results of DRAMI to current clinical practice.17

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Appendix. 

Steering Committee: Enrico Geraci, Roberto Latini, Aldo P. Maggioni, Paolo Marino; Scientific Committee: Fausto Avanzini, Maurizio Bevilacqua, Claudio Borghi, Paolo Chiesi, Paolo Giani, Gian Luigi Nicolosi; Safety and Data Monitoring Committee: Marco De Paolis, Claudio De Vita, Adriano Decarli, Giulio Mingardi; Echo core laboratory: Luigia Bucci, Stefano Ghio, Lidia Staszewsky; Data management and analysis: Giuseppina Di Bitetto Elena Pozzoli, Luigi Santoro, Valter Torri, Violeta Labarta, Francisco Hernandez Bernal; for Chiesi Group, Giovanni Cremonesi.

Clinical Centers/Investigators: Barletta BA (G. Sarcina, F. Cappabianca, A. Galantino); Cagliari (M. Raffo, S. Piras, A.M. Cualbu); Casale Monferrato AL (M. Ivaldi, C. Aletto, G. Gozzelino); Caserta (G. Corsini, M. Schioppa, F. Pietropaolo); Desio MI (S. Gramenzi, G. Foti); Firenze (F. Marchi, M. Milli); Gorizia (A. Fontanelli, G. Giuliano, F. Faggioli); Lavagna GE (M. Brignole, F. Bianchi); Monza MI (F. Valagussa, P. Russo, G. Trocino); Napoli (N. Mininni, S. Wolff, R. Papa); Parma (L. Morozzi, A. Finardi, W. Serra); Pesaro (E. Sgarbi, P. Cesaroni, A. Pierantozzi); Pescara (E. D’Annunzio, G. Rasetti, A. Sciarra); Pistoia (F. Del Citerna, E. Balli, A. Alfieri); Roma (V. Ceci, C. Coletta, G. Greco, A. Galati); Seriate BG (P. Giani, T. Nicoli, V. Giudici); Torino (G.P. Trevi, S. Bergerone, L. Mainardi); Udine (P.M. Fioretti, C. Fresco, P. Gianfagna).

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