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European Heart Journal Advance Access published online on February 8, 2007
European Heart Journal, doi:10.1093/eurheartj/ehl423
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Clinical impact of in-stent late loss after drug-eluting coronary stent implantation{dagger}

Raúl Moreno1,*, Cristina Fernandez2, Angel Sanchez-Recalde1, Guillermo Galeote1, Luis Calvo1, Fernando Alfonso2, Rosana Hernandez2, Rosa Sánchez-Aquino1, Dominick J. Angiolillo2, Sergio Villarreal2, Carlos Macaya2 and Jose L. Lopez-Sendon1

1 Department of Interventional Cardiology, University Hospital La Paz, Paseo La Castellana, 261, 28046 Madrid, Spain
2 Hospital Clinico San Carlos, Madrid, Spain

Received 8 April 2006; revised 22 October 2006; accepted 10 November 2006.

* Corresponding author. Tel: +34 917277545. E-mail address: raulmorenog{at}terra.es


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Comparison among different types...
 References
 
Aims Controversy exists about the clinical significance of in-stent late loss (ISLL) after drug-eluting stent (DES) implantation. We sought to clarify whether ISLL after DES implantation is related to a potential clinical impact.

Methods and results We included in a meta-regression analysis 21 trials (8641 patients) that randomly compared DES with bare-metal stents (BMS). We evaluated the relationship between angiographic behaviour of DES and the clinical impact of using DES instead of BMS in each trial using meta-regression techniques, weighting by the number of patients included in each trial. Mean ISLL in patients allocated to DES and {Delta}ISLL (difference in ISLL in patients allocated to BMS and DES) were used as angiographic parameters of efficacy of DES. The number of patients needed to be treated (NNT) to prevent one target lesion revascularization (TLR) was used to quantify the clinical impact of using DES instead of BMS. There was a significant relationship between mean ISLL in patients allocated to DES and the clinical benefit of using DES instead of BMS, as measured with the NNT for TLR: NNT for TLR = 6.2 + 18.4 [ISLL-DES] (R = 0.62; P = 0.007). Therefore, a 0.1 mm increase in mean ISLL-DES was associated with a 1.8 increase in NNT for TLR. There was also a significant association between the degree of inhibition of neointimal hyperplasia of DES in comparison with BMS with the NNT for TLR: NNT for TLR = 17.1–11.8 [{Delta}ISLL] (R = 0.61; P = 0.008). Therefore, a 0.1 mm reduction in ISLL by using DES instead of BMS was associated with a 1.2 decrease in mean NNT for TLR.

Conclusion There is a strong and significant association between the degree of inhibition of neointimal formation with the use of DES and the clinical impact of using DES instead of BMS.

Key Words: Number of patients needed to treat • Drug-eluting stents • Restenosis


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Comparison among different types...
 References
 
In-stent restenosis due to neointimal formation is the main limitation of bare-metal stents (BMS), as it frequently leads to subsequent revascularization procedures.1 Drug-eluting stents (DES) dramatically reduce both angiographic restenosis and the need for new revascularization procedures by means of inhibiting the formation of neointimal hyperplasia within the stent.2–20

In-stent late loss (ISLL) is a frequently used parameter to quantify the degree of neointimal hyperplasia after coronary stenting.21 It is simple, easy to understand, and very intuitive. ISLL reflects the biological activity of a DES, and currently, it is being used to compare the efficacy of different types of DES in different randomized trials.

Despite all these considerations, the idea that mean ISLL after DES implantation has only limited clinical impact, especially among the range of 0–0.5 mm, has been accepted by many interventional cardiologists, even proposing that only when mean ISLL is higher than 0.5 mm there is a clear increase in the need for new revascularizations.22 This theory is mainly based on rather similar rates of new revascularization procedures after paclitaxel-eluting stent (PES) and sirolimus-eluting stent (SES) implantation despite mean ISLL after PES being approximately two-fold higher than after SES stenting. Additionally, different mean ISLLs have not been translated into different clinical outcomes in some very recent trials that have compared different types of DES.22

The objective of the present study was to clarify whether mean ISLL is related to the clinical impact of using DES instead of BMS. We hypothesized that ISLL is of clinical significance, and that differences in mean ISLL translate into differences in clinical outcome, even within the range of 0–0.5 mm. To test this hypothesis, we performed a meta-regression analysis from randomized trials that have compared DES with BMS. Since the number needed to treat (NNT) is probably the most precise parameter for measuring the clinical benefit associated with a given therapeutic strategy, we evaluated the relationship between mean ISLL and the NNT for new revascularizations.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Comparison among different types...
 References
 
Selection of the studies
In order to identify the trials to be included in the study, we conducted a computerized bibliographic search of the MEDLINE database (National Library of Medicine, Bethesda, MD, USA) and in the abstract supplements of four major scientific meetings—European Society of Cardiology, American College of Cardiology, American Heart Association, and Transcatheter Cardiovascular Therapeutics—until January 2006. We selected all the randomized trials that compared DES and BMS and that provided both follow-up angiographic data and the rate of target lesion revascularization (TLR) for patients allocated to DES and BMS. We included only trials in which coronary stents commercially available in Europe by 2006 were evaluated. We included 21 randomized trials that evaluated the following DES: (i) The SES Cypher (Cordis Corp.): RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS, DIABETES, SCANDSTENT, SES-SMART, STRATEGY, PRISON-II, and the study by Pache et al.;10 (ii) The PES Taxus (Boston Sci.): TAXUS-I, TAXUS-II, TAXUS-IV, TAXUS-V, and TAXUS-VI. As the TAXUS-II evaluated two different release kinetics of paclitaxel (slow-release and moderate-release), each of them with a control group of patients, we analysed these two sub-studies separately; (iii) The tacrolimus-eluting stent (TES) Janus (Sorin Biomedica): JUPITER-II study; (iv) The zotarolimus-eluting stent (ZES) Endeavor (Medtronic Inc.): ENDEAVOR-II trial; and (v) The everolimus-eluting stent (EES, currently the Xience V stent, Guidant Corp.): FUTURE-I, FUTURE-II, and SPIRIT-I trials.2–20

Out of the 21 trials included, two were performed in a single centre, and 19 were multicentred. The blinding of the trial was double in most of the trials, although it was single in SES-SMART, STRATEGY, DIABETES, FUTURE-I, FUTURE-II, SPIRIT-I, and the study by Pache et al.10 Blinding was maintained at quantitative coronary analysis during angiographic follow-up.

Figure 1 shows a patient flow diagram including the number of patients randomized, the number of patients that received standard therapy as allocated, and the number of patients that were followed-up both for BMS and DES arms. Analysis was performed in an intention-to-treat basis in all the trials included. Overall, 8641 patients were randomized (4320 allocated to BMS and 4321 to DES). The proportion of patients that received standard intervention as allocated was similar for BMS and DES (98.7 vs. 98.7%, respectively; P = 0.777), and the proportion of patients that were followed-up for primary endpoint was similar for both groups (95.0 vs. 95.2%, respectively; P = 0.752). Table 1 shows the number of patients included in each study, as well as the main clinical and angiographic characteristics of the population included in the trials.


Figure 4231
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  		Figure 1 Patient flow diagram.

 

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  		Table 1 Main clinical and angiographic baseline characteristics of the trials included in the meta-analysis

 
Definitions and statistical analysis
ISLL was defined as the difference between minimum lumen diameter (MLD) immediately after coronary stent implantation and that obtained at angiographic follow-up, both in DES and BMS groups. As mean values were provided in the trials included, we used the mean value of each trial for the statistical analysis. {Delta}ISLL was calculated as the difference between mean ISLL in patients allocated to BMS and mean ISLL in those allocated to DES in each trial, and reflects the degree of inhibition of neointimal hyperplasia by using DES instead of BMS in each of the studies included.

We used the NNT for new TLR procedures as a measurement of the clinical benefit of using DES instead of BMS in each trial. The NNT is the number of patients who need to be treated in order to prevent one adverse outcome. It is the inverse of the absolute risk reduction (ARR) and was calculated as 1/ARR. ARR was calculated as the difference in the rate of TLR between the control group and the patients allocated to DES in each trial. Although the NNT is usually reported rounded to the next higher whole number, we maintained one decimal for statistical purposes.

The pooled estimates were obtained using the Peto's Assumption Free Method for Combining Trials, and the heterogeneity between groups was assessed by the Q-statistics. The correlation test of Begg and the regression-based test of Egger were used to assess the possible existence of publication bias.

As the objective of the study was to evaluate the relationship between the clinical benefit of using DES instead of BMS (NNT for TLR), head-to-head trials comparing different types of DES were not included for the evaluation of the influence of mean ISLL on the clinical impact of using DES instead of BMS. However, these trials were included when evaluating the relationship between mean ISLL and TLR in each group of patients treated with the same stent in each trial. The head-to-head trials included in this analysis are shown in Table 2, and include the following: SIRTAX, REALITY, ISAR-DESIRE, ISAR-DIABETES, ISAR-SMART-3, CORPAL, ISAR-TEST, and ENDEAVOR-III.23–30


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  		Table 2 Main clinical and angiographic data from head-to-head trials comparing different types of DES

 
Associations between angiographic data (mean ISLL and {Delta}ISLL) and both the incidence of TLR and the clinical benefit of using DES instead of BMS (NNT for TLR) were evaluated by linear regression (Y = {alpha} + ßX), weighting all these associations by the number of patients included in each trial; 95% confidence intervals (CI) for the ß coefficient are provided. Associations were considered statistically significant when the two-tailed P-value was lower than 0.05. The SPSS 12.0 statistical package was used (Chicago, IL, USA).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Comparison among different types...
 References
 
Characteristics of the trials included
No publication bias was detected (Begg's test: P = 0.484; Eggers test: P = 0.137).

Table 1 shows the main angiographic and clinical baseline characteristics of the trials included. Mean reference vessel diameter (RVD) at baseline ranged from 2.20 mm (SES-SMART) to 3.05 mm (FUTURE-I), and lesion length from 9.6 mm (RAVEL) to 20.6 mm (TAXUS-VI). The proportion of diabetic patients ranged from 2 to 100%.

Relationship between ISLL and TLR
There was a significant and strong association between mean ISLL and the proportion of patients undergoing TLR in each allocated group in each trial in trials that randomly compared DES with BMS (Figure 2): TLR = 2.8 + 18.1 (ISLL) (R = 0.82; 95% CI for ß: 13.9, 22.3; P < 0.001). When including also the groups of patients included in head-to-head trials comparing different types of DES, the association between mean ISLL and TRL remained strong and significant: TLR = 4.0 + 16.1 (ISLL) (R = 0.78; 95% CI for ß: 12.5, 19.8; P < 0.001). When including only those allocated groups of patients in which mean ISLL was <0.5 mm, the relationship between mean ISLL and TLR remained statistically significant: TLR = 3.7 + 10.0 (ISLL) (R = 0.40; 95% CI for ß: 1.0, 18.9; P = 0.030).


Figure 4232
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  		Figure 2 Relationship between ISLL and TLR in each treatment group in randomized trials that have evaluated DES. The figure displays data from randomized trials comparing DES and BMS, and also from head-to-head studies comparing different types of DES.

 
There was also a significant association between the proportion of patients with binary angiographic restenosis (BAR) and the rate of TLR: TLR = 3.38 + 0.48 [BAR] (R = 0.86; 95% CI for ß: 0.39, 0.57; P < 0.001). When including also data from the head-to-head trials comparing different types of DES, the linear regression was very similar: TLR = 3.3 + 0.48 [BAR] (R = 0.85; 95% CI for ß: 0.40, 0.56; P < 0.001).

Benefit of using DES instead of BMS
Data on mean ISLL for each study are shown in Table 3. In all trials except the JUPITER-II, mean ISLL was significantly lower in patients allocated to DES. Mean ISLL ranged from 0.63 to 1.09 mm in patients allocated to BMS, and from –0.01 to 0.63 mm in those allocated to DES. {Delta}ISLL ranged from 0.00 to 1.04 mm.


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  		Table 3 Follow-up angiographic data in the trials included in the meta-analysis

 
Rates of BAR, TLR, as well as the calculated NNT for each of these endpoints are also reported in Table 3. In all the trials, BAR occurred less frequently in patients allocated to DES, but the degree of clinical benefit (NNT) widely varied among the studies. NNT for binary restenosis ranged from 2.2 to 15.6, and NNT for TLR from 3.7 to 22.2. Figure 3 shows mean data of ISLL in patients allocated to DES, and angiographic ({Delta}ISLL and NNT for BAR), and clinical benefit (NNT for TLR) of using DES instead of BMS. Among all the types of DES evaluated in the trials included, the SES stent showed the highest {Delta}ISLL, and the lowest NNT for both BAR and TLR. In contrast, the TES stent showed the lowest {Delta}ISLL, and the highest NNT for both BAR and TLR.


Figure 4233
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  		Figure 3 Angiographic (ISLL in patients allocated to DES, {Delta}ISLL, and NNT for BAR) and clinical (NNT for TLR) benefit of using DES instead of BMS for each type of DES evaluated in the trials included in the meta-analysis. *P < 0.05.

 
Relationship between mean ISLL and the clinical impact of using DES
There was a significant relationship between mean ISLL in patients allocated to DES and the clinical benefit of using DES instead of BMS, as measured with the NNT for TLR (Figure 4): NNT for TLR = 6.2 + 18.4 [ISLL-DES] (R = 0.62; 95% CI for ß: 5.8, 31.0; P = 0.007). Therefore, a 0.1 mm increase in ISLL-DES was associated with a 1.8 increase in NNT for TLR. The association remained significant after adjusting by the proportion of diabetic patients (NNT for TLR = 8.0 + 17.3 [ISLL-DES]–0.002 [% of diabetics]; R = 0.66; 95% CI for ß: 4.9, 25.1; P = 0.006), by the mean RVD (NNT for TLR = –11.7 + 12.0 [ISLL-DES] + 6.6 [mean RVD]; R = 0.59; 95% CI for ß: 1.1, 23.1; P = 0.034) or the mean lesion length in each trial (NNT for TLR = 13.7 + 17.2 [ISLL-DES]–0.6 [mean lesion length]; R = 0.70; 95% CI for ß: 7.5, 26.8; P = 0.002).


Figure 4234
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  		Figure 4 Relationship between the ISLL in patients allocated to DES, and the number of patients needed to prevent one TLR in each trial. Results are adjusted by the number of patients included in each trial.

 
When considering the degree of reduction of neointimal hyperplasia associated with the use of DES instead of BMS ({Delta}ISLL) as independent variable, there was a significant association between {Delta}ISLL and the clinical benefit of using DES instead of BMS (Figure 5): NNT for TLR = 17.1 – 11.8 [{Delta}ISLL] (R = 0.61; 95% CI for ß: –20.1, –3.6; P = 0.008). Therefore, a 0.1 mm increase in {Delta}ISLL (a 0.1 mm reduction in mean ISLL by using DES instead of BMS) is associated with a 1.2 decrease in NNT for TLR. Using {Delta}ISLL instead of ISLL has the advantage of adjusting by the ISLL in patients allocated to BMS in each study. This association remained statistically significant after adjusting by the proportion of diabetic patients (NNT for TLR = 23.3–12.7 [{Delta}ISLL] –1.0 [% of diabetics]; R = 0.72; 95% CI for ß: –19.7, –5.7; P = 0.001), the mean RVD (NNT for TLR = –5.1–10.8 [{Delta}ISLL] + 7.8 [mean RVD]; R = 0.61; 95% CI for ß: –19.8, –1.7; P = 0.023) or the mean lesion length in each trial (NNT for TLR = 21.2–11.5 [{Delta}ISLL] –0.31 [mean lesion length]; R = 0.64; 95% CI for ß: –19.4, –3.6; P = 0.007).


Figure 4235
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  		Figure 5 Relationship between the reduction of ISLL in patients allocated to DES in comparison with those allocated to BMS ({Delta}ISLL), and the number of patients needed to prevent one TLR in each trial. Results are adjusted by the number of patients included in each trial.

 
When using in-segment late loss (ISGLL) instead of ISLL as angiographic parameter, the clinical implications of differences in ISGLL were also significant: NNT for TLR = 5.8 + 19.1 [ISGLL in DES] (R = 0.71; 95% CI for ß: 2.8, 35.4; P = 0.026); and NNT for TLR = 15.8–15.2 [delta ISGLL in DES] (R = 0.84; 95% CI for ß –23.2, –7.3; P = 0.002).

There was also a significant and strong association between the NNT for BAR and the NNT for TLR in each trial: NNT for TLR = 1.01 + 1.28 [NNT for BAR] (R = 0.86; 95% CI for ß: 0.89, 1.66; P < 0.001).


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
Comparison among different types...
 References
 
Benefit of DES over BMS
The leading mechanism of in-stent restenosis after BMS is late loss due to in-stent neointimal formation, whereas both elastic recoil and negative remodelling are virtually eliminated by stent scaffolding.1 DES have recently revolutionized interventional cardiology, since they have demonstrated to reduce both BAR and the need for subsequent revascularization procedures2–20 without increasing the risk of stent thrombosis, at least during the first year and under prolonged double anti-platelet therapy,31 although the possible effect of DES over the risk of very late (>1 year) stent thrombosis is still to be quantified.

ISLL as a surrogate of DES effectiveness
BAR (presence of stenosis severity > 50% at 6–9 month follow-up) has been the most commonly used angiographic parameter in order to compare different devices in interventional cardiology. However, continuous measurements, such as MLD, percent diameter of stenosis, and late loss, have the advantage of being able to quantify more precisely the long-term angiographic benefit of a therapeutic mean, thus necessitating less patients to demonstrate the efficacy of a given device. As it is very intuitive, appealing from a mechanistic point of view, and not referred to RVD, ISLL has been used in many DES trials. ISLL reflects the biological effect (inhibition of neointimal formation) of DES in a very precise way, and because of that it is now being used as a surrogate endpoint in some randomized trials that are comparing different types of DES.

However, despite these considerations, many authors believe that the clinical implications of ISLL are limited, taking into account some recent findings from some randomized trials. First, data from the TAXUS-IV study have suggested that only when ISLL exceeds 0.5 mm there is an increase in the need for TLR, whereas mean ISLL lower than 0.5 is associated with extremely low rates of TLR, arguing also that coronary stents may accommodate an up to 0.5 mm ISLL inside the stent without increasing the need for new revascularizations.22 Second, different types of DES have been associated with different ISLL values (0.17, 0.39, and 0.62 mm in the SIRIUS, TAXUS-IV, and ENDEAVOR-II trials, respectively), but rather similar rates of TLR (4.0, 3.0, and 4.6%, respectively).3,14,17 Finally, some recent trials comparing different types of DES have shown some discrepancies between angiographic and clinical data. For example, in the recently reported ENDEAVOR-III trial, where ZES and SES were randomly compared, mean ISLL was much lower in patients allocated to SES (0.15 vs. 0.60 mm), but the rates of target vessel revascularization were not significantly different (5.3 vs. 6.0%, respectively).30

Our results show that mean ISLL is associated with the degree of clinical benefit of using DES instead of BMS, quantified as the NNT for TLR. NNT is probably the best parameter for measuring the clinical impact of a given therapy. Lower mean ISLL was associated with lower NNT for TLR. An important finding of our study was that the clinical implications of mean ISLL are present even within the range of mean ISLL lower than 0.5 mm (most trials included had a mean ISLL lower than 0.5 mm in patients allocated to DES).

Because BAR rates after DES implantation are lower than that for BMS, and low binary event rates result in decreased statistical power in randomized trials, the number of patients needed to make comparisons between new and proven DES has increased substantially. As ISLL is a continuous endpoint, it allows to compare the efficacy of different types of DES without the necessity of using extremely large populations of patients. In a recent study, Mauri et al.32 have demonstrated that ISLL is strongly correlated with the rates of both BAR and TLR when using DES. In the present study, we have extended this relationship to the degree of clinical benefit of using DES instead of BMS (NNT for TLR). Moreover, by using {Delta}ISLL, we have adjusted mean ISLL in patients allocated to DES by the angiographic behaviour of the respective BMS, thus demonstrating that the degree of inhibition of neointimal formation after stenting by the use of DES is strongly associated with the clinical impact of using DES instead of BMS.


   Comparison among different types of DES
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Comparison among different types...
References
 
This meta-regression analysis evaluated the relationship between angiographic behaviour of DES and the clinical benefit of using DES instead of BMS, but not the comparison between different types of DES. Our present study therefore does not allow to obtain conclusions about comparison of different types of DES. However, our findings suggest that among all the different types of DES evaluated in the trials included, the SES shows the most evident angiographic and clinical benefit when used instead of BMS. Studies that compared BMS with the SES showed the lowest NNT for BAR and also for TRL. Considering the NNT for TLR as the measurement of the clinical benefit of using DES instead of BMS, this benefit was progressively reduced in SES, PES, EES, ZES, and TES (mean NNT for TLR 6.8, 11.9, 11.1, 13.3, and 20.4, respectively) (Figure 3).

SES and PES are the most widely used DES, due to their proven efficacy in reducing TLR in comparison with BMS in a large number of randomized trials.2–16 Several randomized trials have compared these two types of DES, with discordant results.23–28,33 Although angiographic follow-up was more favourable with SES in most cases, clinical differences were obtained only in some of them. A possible reason for these discordant results may be the inclusion of higher risk patients in some trials such as ISAR-DESIRE and ISAR-DIABETES, in comparison with others such as the REALITY study. We have recently performed a meta-analysis from the TAXI, REALITY, ISAR-DESIRE, ISAR-DIABETES, and SIRTAX trials.34 We found that TLR was significantly lower in patients allocated to SES in comparison with PES (5.0 vs. 7.4%, P < 0.01), and the same occurred with target vessel revascularization (6.1 vs. 8.3%, P = 0.02) and BAR (9.0 vs. 12.4%, P = 0.002), whereas the risk of stent thrombosis was similar. Consistent results have been recently reported by Kastrati et al.,35 in which the CORPAL trial was also included. The superiority of the SES in reducing the rate of BAR and TLR is probably explained to the higher reduction of ISLL. Several factors may be related with this different angiographic behaviour after SES or PES. First, sirolimus and paclitaxel have different mechanism of action (whereas sirolimus is cytostatic, paclitaxel is cytotoxic). Second, both types of DES have different drug-release kinetics (the polymer coating of SES allows the elution of nearly 100% of the drug within 1 month, whereas in the case of PES the polymer allows the eluting of only 10% of the drug over 2 months, with 90% of paclitaxel remaining sequestered in the polymer indefinitely). Finally, both stents have different designs: a closed-cell design in the case of SES, and an open-cell design in the case of PES.35

Head-to-head trials comparing newer DES with either Cypher or Taxus are still scarce. The ENDEAVOR-III trial has not shown statistically significant differences between patients allocated to ZES or SES in terms of TLR. However, owing to the study design (3:1 randomization), the number of patients allocated to PES was low.30 In the ISAR-TEST trial, a non-polymer on-site coating with rapamycin (Yukon stent) was not inferior to PES in 450 patients. Other head-to-head randomized trials, such as SPIRIT-II (Xience V [Guidant Corp.] vs. Taxus), ZOMMAX I (zotarolimus-eluting Zommax stent [Abbott] vs. Taxus), or NOBORI I (biolimus-eluting Nobori stent [Terumo] vs. Taxus) are currently ongoing.

Study limitations
First, the present study has the inherent limitations of meta-regression techniques, such as the possibility of having missed some confounder variables.36 Second, ISLL may vary among different stent platforms, and thus the use of different BMS in the trials included may have influenced the results. However, in order to prevent any bias related with differences among different types of BMS, we also used {Delta}ISLL as a measurement of the angiographic benefit of DES. Third, ISLL may also vary among different core laboratories, but this limitation was also overcome by the use of {Delta}ISLL, since angiographic data from patients included both in DES and BMS groups were measured in the same core laboratory in each trial. Fourth, ISLL may vary with some patient and lesion characteristics, such as the presence of diabetes, RVD, or lesion length. The results of the meta-regression analysis, however, were maintained after adjusting for these variables. Finally, routine angiographic follow-up may influence the rate of TLR, and it could be speculated that the NNT for TLR might be higher in all trials in case the routine angiographic follow-up was not performed.

Conflict of interest: none declared.


   Footnotes
 
{dagger} Presented in part at the Scientific Sessions of the American Heart Association, Dallas, TX, USA, November 2005. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Comparison among different types...
 References
 

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