Coronary collateral growth by external
counterpulsation: a randomised controlled trial

Steffen Gloekler, Pascal Meier, Stefano F de Marchi, et al.
2010 96: 202-207 originally published online November 5, 2009 Updated information and services can be found at: References
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To order reprints of this article go to: Coronary collateral growth by externalcounterpulsation: a randomised controlled trial Steffen Gloekler, Pascal Meier, Stefano F de Marchi, Tobias Rutz, Tobias Traupe,Stefano F Rimoldi, Kerstin Wustmann, He ´le`ne Steck, Ste´phane Cook, Rolf Vogel, occlusion duration, the option of reducing infarct Background The efficacy of external counterpulsation size by collateral artery growth promotion is (ECP) on coronary collateral growth has not been investigated in a randomised controlled study.
Collateral growth is triggered by increased Correspondence toProfessor Christian Seiler, Objective To test the hypothesis that ECP augments tangential fluid shear stress at the endothelium, the collateral function during a 1 min coronary balloon product of spatial flow velocity changes during the cardiac cycle and blood viscosity.4 Lower-leg, high- Patients and methods Twenty patients with chronic pressure external counterpulsation (ECP) triggered stable coronary artery disease were studied. Before and after 30 h of randomly allocated ECP (20 90 min sessions signal and thus, tangential endothelial shear stress over 4 weeks at 300 mm Hg inflation pressure) or sham in addition to the flow signal caused by cardiac ECP (same setting at 80 mm Hg inflation pressure), the stroke volume. In this context and particularly invasive collateral flow index (CFI, no unit) was obtained because of the relevance of diastolic flow augmen- in 34 vessels without coronary intervention. CFI was tation for the coronary circulation. ECP has been determined by the ratio of mean distal coronary occlusive shown to improve myocardial blood flow and to pressure to mean aortic pressure with central venous ease related symptoms.5 ECP has been repetitively pressure subtracted from both. Additionally, coronary hypothesised but not investigated in a randomised collateral conductance (occlusive myocardial blood flow controlled fashion with regard to coronary arterio- per aorto-coronary pressure drop) was determined by myocardial contrast echocardiography, and brachial Therefore, the goal of this study in patients with artery flow-mediated dilatation was obtained.
chronic stable CAD was to test the hypothesis that Results CFI changed from 0.125 (0.073; interquartile range) at baseline to 0.174 (0.104) at follow-up in theECP group (p¼0.006), and from 0.129 (0.122) to 0.111 (0.125) in the sham ECP group (p¼0.14). Baseline to follow-up change of coronary collateral conductance was Twenty patients with chronic stable one- (n¼3), from 0.365 (0.268) to 0.568 (0.585) ml/min/100 mm Hg two- (n¼9) or three-vessel (n¼8) CAD (stable, in the ECP group (p¼0.072), and from 0.229 (0.212) to exercise- or stress-induced angina pectoris) eligible 0.305 (0.422) ml/min/100 mm Hg in the sham ECP group for percutaneous coronary intervention (PCI) of at (p¼0.45). There was a correlation between the flow- least one stenotic lesion were included in the study.
mediated dilatation change from baseline to follow-up All underwent diagnostic coronary angiography and the corresponding CFI change (r¼0.584, p¼0.027).
because of symptoms related to CAD. Patients were Conclusions ECP appears to be effective in promoting prospectively selected on the basis of the following coronary collateral growth. The extent of collateral criteria: (1) no previous transmural infarction in the function improvement is related to the amount of myocardial areas assessed for coronary collaterals, improvement in the systemic endothelial function.
(2) normal left ventricular ejection fraction, (3) nocongestive heart failure, (4) no baseline ECG ST-segment abnormalities, (5) no aortic regurgitation, (6) no lower-leg deep vein thrombosis as assessed by Cardiovascular disease is the leading cause of death duplex sonography, (7) no atrial fibrillation or in industrialised countries and may become the frequent supraventricular or ventricular beats.
most important reason for mortality world wide.1 Patients were randomly assigned to lower-leg, In patients with coronary artery disease (CAD), the high-pressure (300 mm Hg cuff inflation pressure; size of myocardial infarction mainly determines ECP group, n¼10) or low-pressure (80 mm Hg cuff outcome after such an event.2 Accordingly, it is the inflation pressure; sham ECP group, n¼10) ECP primary strategy to reduce cardiovascular mortality treatment with a total of 20 90 min sessions (¼30 h; by shrinking infarct size. Infarct size is directly 5 days a week, 4 weeks). The randomisation scheme influenced by the following factors: duration of in two block sizes of 10 was generated using coronary occlusion, ischaemic area at risk for the website (http://www.
infarction, lack of collateral blood supply to the, accessed November 2009) ischaemic zone, absence of ischaemic preconditioning before the study began, whereby a study nurse, but before the infarct, myocardial oxygen consumption not the investigators performing the study during the infarct.3 Aside from curtailing coronary measurements and data analyses, were aware of the Heart 2010;96:202e207. doi:10.1136/hrt.2009.184507 randomisation key. Collateral function and absolute myocardial was selected for CFI measurements. This vessel underwent PCI perfusion were assessed during balloon occlusion in a stenotic following ECP treatment. Additionally, and if suitable, an angio- and, if possible, in an angiographically and functionally normal graphically and functionally normal coronary artery was selected for coronary artery at baseline before and immediately after the CFI measurement (normal vessel). In both arteries, fractional flow reserve was determined for functional assessment with the pressure This investigation was approved by the institutional ethics guidewire positioned distally in the vessel using a bolus of intra- committee, and the patients gave written informed consent to coronary adenosine (12 µg for the right, 18 µg for the left coronary artery) for induction of hyperaemia. At baseline and follow-up, anadequately sized angioplasty balloon catheter (10e20 mm in length, Cardiac catheterisation and coronary angiography diameter ranging from 2.5 to 4 mm) was positioned proximal to the Patients underwent left heart catheterisation for diagnostic stenosis to be dilated, and at a proximal location in the normal vessel, purposes from the right femoral approach. Aortic pressure was while the pressure guidewire was positioned distally in the respective measured using a 6F PCI guiding catheter. Central venous vessels. Balloon inflation for collateral measurement before ECP pressure (CVP) was obtained via the right femoral vein. Left treatment occurred in the proximal, non-stenotic vessel segment at ventricular end-diastolic pressure was determined before PCI.
a pressure of 1e2 atmospheres. During this vessel occlusion, simul- Biplane left ventriculography was performed followed by taneous Poccl, Pao and CVP were obtained for the calculation of CFI.
biplane coronary angiography. Coronary artery stenoses were The initial invasive procedure was followed by 30 h of ECP treat- determined quantitatively as percentage diameter narrowing ment at high or low cuff inflation pressure starting the day after the (>50% diameter reduction being a relevant stenosis severity).
baseline procedure. The patients and the investigators performingthe study measurements and data analyses were blinded to the ECP study group assignment (ECP sessions performed by a study nurse).
All drugs were left unaltered during the study period. The invasive Coronary collateral flow relative to normal antegrade flow follow-up examination immediately after the treatment period through the non-occluded coronary artery (collateral flow index, consisted of intracoronary measurements identical to those described CFI) was determined using coronary pressure measurements. A above. PCI of the stenotic lesion initially selected for dilatation was 0.014 inch pressure monitoring angioplasty guidewire (Pressure performed immediately after the follow-up measurements.
Wire, Radi, Uppsala, Sweden) was set at zero, calibrated, Absolute myocardial blood flow at rest and during hyperaemia in advanced through the guiding catheter and positioned in the the areas supplied by the coronary arteries of interest was obtained distal part of the vessel of interest. CFI was determined by using contrast echocardiography at baseline and at follow-up simultaneous measurement of mean aortic pressure (Pao, mm simultaneously with the invasive procedures. Hyperaemia was Hg), distal coronary artery pressure during balloon occlusion induced by intravenous adenosine (140 µg/min/kg), and myocar- (Poccl, mm Hg), and the CVP (mm Hg). CFI was calculated as dial perfusion reserve was calculated as absolute blood flow during hyperaemia divided by blood flow at rest (both in ml/min/g). Inaddition, myocardial blood flow at rest was also obtained during coronary occlusion simultaneously with the CFI measurement.
Absolute myocardial perfusion or blood flow at rest and duringhyperaemia was assessed quantitatively using myocardial contrast echocardiography (MCE; Acuson Sequoia 512, Acuson Sample size calculation was based on the assumption of Siemens, Mountain View, California, USA), whereby a previ- detecting an increase during follow-up in CFI of at least 50% in ously described and validated algorithm was employed.10 Briefly, the ECP group as compared with the sham ECP group. At for the calculation of absolute blood flow, the constituent factors, a statistical power of 80%, the number of vessels to be measured relative myocardial blood volume rBV and its refill rate was estimated to be 30. Since in the majority of patients, CFI following destruction of echo contrast microbubbles, were would be obtainable in >1 vessel, the number of patients esti- obtained during vessel patency. Myocardial blood flow is equal to mated to be included in the study was 20.
the product of rBV and b divided by myocardial tissue density.10 Continuous data are given as median and interquartile range.
Absolute myocardial blood flow at rest was also determined Baseline characteristics between the groups were analysed by during coronary occlusion, thereby allowing the calculation of a ManneWhitney U test for continuous data and by c2/ Fisher’s coronary collateral conductance (myocardial blood flow/ exact tests for categorical data. Within-group analyses at different time points were performed by a Wilcoxon signed rank As a parameter characterising the functional influence of the test. Between-group comparison of treatment-induced changes added shear rate signal by ECP on the circulation, right brachial of continuous end points was performed by a ManneWhitney U artery flow-mediated vasodilatation (FMD) was determined test. Linear regression analysis was used for the comparison of before and after ECP treatment by two-dimensional vascular ECP-induced CFI changes and corresponding FMD changes.
Continuous values are given as median and interquartile range.
Differences were considered statistically significant at a two- sided p value of <0.05. Statistical analysis was performed using FMD measurement was performed while fasting before and after ECP treatment (before PCI) during a session separate fromthe invasive procedure.
At the start of both baseline and follow-up invasive procedures, all patients received 5000 units of heparin intravenously. Following Patient characteristics and clinical data at baseline diagnostic examinations, two puffs of oral isosorbide dinitrate were The two groups had similar key baseline characteristics, such as given. The coronary artery regarded as the lesion responsible for the age, gender, cardiovascular risk factors and cardiovascular patient’s symptomsdthat is, the one with the most severe stenosis, Heart 2010;96:202e207. doi:10.1136/hrt.2009.184507 History of prior myocardial infarction (%) Family history of coronary artery disease Data are given as median (interquartile range) for continuous variables.
CFI, collateral flow index; ECP, external counterpulsation; LAD, left anterior descending artery; LCX, left circumflex coronary artery; RCA, right coronary artery.
amounted to +0.069 (0.128) in the ECP group and to À0.017 (0.049) in the sham ECP group (p¼0.0009). The respective numbers in the 20 study patients focusing on stenotic vessels were +0.104 (0.095) in the ECP group and À0.034 (0.122) in the BMI, body mass index; CCS, Canadian Cardiovascular Society; ECP, external MCE-derived myocardial blood flow reserve in the region subtended by the vessels in which CFI was obtained changed from1.51 (0.96) at baseline to 2.06 (1.22) in the ECP group (p¼0.11), and Invasive and haemodynamic data at baseline from 1.26 (1.99) at baseline to 2.11 (2.95) in the sham ECP group Haemodynamic and angiographic data at baselinedthat is, (p¼0.40). Resting coronary collateral conductance as obtained by systemic blood pressure, heart rate, left ventricular ejection MCE during vessel occlusion increased from 0.365 (0.268) at fraction and end-diastolic pressure, the structural and functional baseline to 0.568 (0.585) ml/min/100 mm Hg at follow-up in the (fractional flow reserve) severity of CAD were not significantly ECP group (p¼0.072), and from 0.229 (0.212) at baseline to 0.305 different between the groups (table 2).
(0.422) ml/min/100 mm Hg at follow-up in the sham ECP group The stenotic and the normal vessels undergoing CFI (p¼0.45; figure 2). Right brachial artery FMD increased from 4.3% measurement as well as the CFI measurement site were similarly (1.5) at baseline to 6.9% (3.5) at follow-up in the ECP group distributed between the groups. CFI values at baseline did not (p¼0.018), and from 6.0% (3.0) at baseline to 7.6% (3.5) at follow- differ significantly (table 2). Right brachial artery diameter was up in the sham ECP group (p¼0.10). The absolute change in FMD 4.1 (1.1) mm in the ECP group and 4.0 (1.3) mm in the sham ECP from baseline to follow-up as obtained in all vessels amounted to group (p¼0.44). Right brachial artery flow-mediated dilatation +1.75% (2.8) in the ECP group and to +0.50% (1.0) in the sham was 4.3% (1.5) in the ECP group and 6.0% (3.0) in the sham ECP ECP group (p¼0.07). There was a direct correlation between the group (p¼0.14). Myocardial blood flow reserve at baseline as FMD change from baseline to follow-up and the corresponding determined by MCE was 1.51 (0.96) in the ECP group and 1.26 (1.99) in the sham ECP group (p¼0.56).
In the ECP group, fractional flow reserve increased from Treatment-induced changes of study end points baseline to follow-up from 0.85 (0.13) to 0.91 (0.07) (p¼0.05), whereas it changed from 0.88 (0.07) at baseline to 0.87 (0.04) CFI values as obtained in 34 normal and stenotic vessels changed from 0.125 (0.073) at baseline to 0.174 (0.104) at follow-up inthe ECP group (n¼15; p¼0.006), and from 0.129 (0.122) to 0.111 (0.125) in the sham ECP group (n¼19; p¼0.14; figure 1). CFI This randomised controlled clinical study in patients with values as obtained in the stenotic vessels of the 20 patients chronic stable CAD documents that ECP improves collateral changed from 0.098 (0.102) at baseline to 0.173 (0.071) at follow- function to a briefly occluded vessel. The level of CFI improve- up in the ECP group (p¼0.003), and from 0.129 (0.164) to 0.109 ment in response to ECP treatment is directly related to the (0.090) in the sham ECP group (p¼0.121). The absolute change in induced change of endothelium-dependent brachial artery CFI from baseline to follow-up as obtained in all vessels Heart 2010;96:202e207. doi:10.1136/hrt.2009.184507 collateral flow index (vertical axes) from (ECP; left panel; black lines) and to sham ECP (right panel; red lines). Red linesindicate mean values6SD.
Collateral flow index (no unit)
uncontrolled investigation in patients with CAD who were More than half a century ago, Kantrowitz described diastolic initially allocated to ECP and later to a control group without augmentation of aortic perfusion pressure as a way to increase ECP.7 Patients in the ECP group showed a significant increase in coronary blood flow.12 Diastolic pressure augmentation by ECP coronary pressure-derived CFI; there was no change in CFI in the at a pressure of 300 mm Hg results in an increase in diastolic and control group. Also similar to our study, fractional flow reserve mean aortic and coronary pressure, a decrease in systolic pressure increased in the ECP group but not in the control group.
and an increase in coronary Doppler flow velocity.13 So far, there Our study verifies the positive effect of ECP on the coronary has been only one controlled clinical trial investigating the effect collateral circulation in several ways. The primary study end of ECP versus sham ECP, showing a benefit of the former on the point, CFI, improves in response to ECP in an unexpected severity of angina pectoris, on the use of glyceryl trinitrate, on magnitude, in comparison with other forms of coronary collat- physical exercise capacity, and on the time to ECG ST-segment eral growth promotion in humans (eg, colony stimulating depression during exercise;14 myocardial perfusion was not factors16 17). Coronary collateral conductancedthat is, the obtained in that study. More than a dozen other studies on the reference parameter describing tissue perfusion in experimental same subject have employed an uncontrolled design.5 Accord- studies, is augmented likewise in the ECP group. Collateral ingly, the European Society of Cardiology views ECP as a prom- conductance obtained by MCE was measured independently of, ising modality with more clinical trials needed to define its role in and simultaneously with, the invasive CFI assessment. In a clin- treating refractory angina pectoris.15 Masuda and coworkers6 ical study, this is unique and unprecedented, because other sought to elucidate the mechanism by which ECP exerts its modalities to obtain absolute tissue perfusion in humans do not beneficial effects on chronic angina pectoris. Using [13N] allow such measurements to be performed during a brief artificial ammonia positron emission tomography, they found in 11 coronary balloon occlusion. Myocardial blood flow reserve as patients undergoing 35 1 h sessions of ECP that myocardial obtained during vessel patency and before PCI, and thus perfusion at rest and in response to dipyridamole was increased representing changes in collateral flow, points in the same at the end of the treatment (myocardial blood flow reserve change from 1.7560.24 to 2.0860.28).6 Myocardial blood flowreserve in response to ECP serves as an ‘anchor’ parameter for Underlying pathogenetic principle of physical collateral growth comparison in the context of our study, in which a numerically similar, but insignificant increase was found in the ECP group. In Since fluid shear stress, the trigger of arteriogenesis, is the the study by Masuda et al,6 an augmented coronary collateral product of the spatial flow velocity change between different circulation aside from reduced ventricular after load has been fluid layers (dv/ds¼shear rate) and the blood viscosity, and hypothesised to play the central role in the mechanism, whereby because the latter can be regarded as remaining constant over the ECP exerts its benefits. However so far, the collateral or arterio- course of 4 weeks, the focus with regard to physical forms of genesis hypothesis has never been tested in a randomised collateral growth is on the amplitude, duration and number controlled trial. Very recently, Buschmann et al performed an of flow velocity signals per cardiac cycle operative at the (ECP; left panel; black lines) and to shamECP (right panel; red lines). Red lines (ml/min/100mmHg) 0.20
Collateral conductance
Heart 2010;96:202e207. doi:10.1136/hrt.2009.184507 between ECP-induced improvement in brachial artery endothe-lial and coronary collateral function. The functional parameter of myocardial blood flow reserve, a parameter obtained in this study by myocardial contrast echo behaved similar to FMD withoutreaching statistical significance.
The main limitation of this study is its small sample size. Thus, despite the unexpectedly marked effect of ECP on collateralfunction, the findings should be interpreted as proof of concept ECP group:
that ECP might promote coronary collateral growth rather than Delta collateral flow index
(follow-up minus baseline) -.15
definite evidence of efficacy. Data are even more limited with r=0.584, p=0.0273
regard to the secondary end point of FMD.
The principal explanation for the incomplete agreement Delta flow-mediated dilation
between contrast-echo-derived myocardial blood flow reserve (%; follow-up minus baseline)
and FMD, respectively, between collateral conductance and CFIis mainly related to the difficult examination conditions for Correlation between the change during follow-up in brachial transthoracic echocardiography with the patient lying on his artery flow-mediated dilatation (horizontal axis) and the corresponding back on the catheterisation laboratory table. In comparison with change in collateral flow index (vertical axis). Cross symbols: external the usual left lateral supine position, respiratory artefacts impair counterpulsation (ECP) group; blue dots: sham ECP group.
the ultrasound image quality much more in the supine backposition.
endothelium. Hence, the following classes of physical collateralgrowth promotion can be distinguished: increased cardiac output Acknowledgements Supported by a grant from the Swiss National Science (augmented flow rate with a respective increase in flow velocity), extended duration of diastole and added number of diastolic flow Contributors SG, PM, SFdM contributed equally to this study. All authors have velocity signals. Both endurance exercise training respectively substantially contributed to the work.
ECP treatment can be categorised accordingly as temporary and Funding Swiss National Science Foundation for Research, Bern, Switzerland.
repetitive increase in cardiac output, respectively, added shear rate signals. Alternatively, the prolonged diastole at rest inducedby the training could be responsible for the arteriogenic effect of Ethical approval This study was conducted with the approval of the Kantonale physical exercise. For the sake of the argument, the term arte- riogenesis can be used in a broader sense than collateral growth Provenance and peer review Not commissioned; externally peer reviewed.
promotiondnamely, as general arterial calibre growth. In thelatter context, there have been a number of studies confirming the concept of ‘arteriogenesis’ in response to augmented shear Lopez A, Mathers C, Ezzati M, et al. Global and regional burden of disease and risk ratedfor example, through exercise training.18 19 Similarly, the factors, 2001: systematic analysis of population health data. Lancet added shear rate signal during diastole with ECP is probably Sobel BE, Bresnahan GF, Shell WE, et al. Estimation of infarct size in man and its responsible for its arteriogenic effect. Two related questions relation to prognosis. Circulation 1972;46:640e7.
arising in the context of this study are: does the diastolic shear Reimer KA, Ideker RE, Jennings RB. Effect of coronary occlusion site on ischaemic rate signal present also in the sham ECP group have an amplitude bed size and collateral blood flow in dogs. Cardiovasc Res 1981;15:668e74.
insufficient to induce collateral growth? and do we have data Heil M, Schaper W. Insights into pathways of arteriogenesis. Curr Pharm Biotechnol2007;8:35e42.
from this study supporting the arteriogenic mechanism operative Manchanda A, Soran O. Enhanced external counterpulsation and future directions: in ECP just alluded to? Regarding CFI, the diastolic low-velocity step beyond medical management for patients with angina and heart failure. J Am Coll signal caused by the 80 mm Hg inflation pressure sham ECP Masuda D, Nohara R, Hirai T, et al. Enhanced external counterpulsation improved appears to be inadequate to augment collateral function.
myocardial perfusion and coronary flow reserve in patients with chronic stable angina; However, and with respect to brachial artery FMD, there is evaluation by(13)N-ammonia positron emission tomography. Eur Heart J a trend towards improved endothelial function in the sham ECP Buschmann E, Utz W, Pagonas N, et al. Improvement of fractional flow reserve and group. Is brachial artery FMD an adequate marker to support the collateral flow by treatment with external counterpulsation (Art.Net.-2 Trial). Eur J Clin hypothesised mechanism of augmented fluid shear stress by Seiler C, Fleisch M, Garachemani A, et al. Coronary collateral quantitation in patients FMD is a parameter of arterial endothelial function, whereas with coronary artery disease using intravascular flow velocity or pressuremeasurements. J Am Coll Cardiol 1998;32:1272 arteriogenesis is primarily a structural process resulting in Vogel R, Zbinden R, Indermuhle A, et al. Collateral-flow measurements in humans by functional improvement of arterial conductance. However, myocardial contrast echocardiography: validation of coronary pressure-derived vasodilatation is the first step in the pathogenesis of collateral collateral-flow assessment. Eur Heart J 2006;27:157e65.
Vogel R, Indermuhle A, Reinhardt J, et al. The quantification of absolute myocardial growth and occurs in response to augmented tangential shear perfusion in humans by contrast echocardiography: algorithm and validation. J Am Coll stress owing to an increased pressure gradient between the source of preformed collaterals and their orifice in the stenotic epicardial Corretti M, Anderson T, Benjamin E, et al. Guidelines for the ultrasound assessment artery. Accordingly, the necessary condition for arteriogenesis of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report ofthe International Brachial Artery Reactivity Task Force. J Am Coll Cardiol induced by augmented vascular shear stress, improved endothe- lial function, could be observed in a circulatory region remote Kantrowitz A. Experimental augmentation of coronary flow by retardation of the from the coronary arteries using a method which allowed also arterial pressure pulse. Surgery 1950;34:678e87.
Michaels A, Accad M, Ports T, et al. Left ventricular systolic unloading and the visualisation of the added flow velocity signal caused by ECP.
augmentation of intracoronary pressure and Doppler flow during enhanced external More importantly, our study revealed a direct association counterpulsation. Circulation 2002;106:1237e42.
Heart 2010;96:202e207. doi:10.1136/hrt.2009.184507 Feldman A, Silver M, Francis G, et al. Enhanced external counterpulsation improves Meier P, Gloekler S, de Marchi S, et al. Myocardial salvage through coronary exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol collateral growth by granulocyte colony-stimulating factor in chronic coronary artery disease: a controlled randomized trial. Circulation 2009;120:1355e63.
Fox K, Garcia M, Ardissino D, et al. Guidelines on the management of stable angina Seiler C, Kirkeeide RL, Gould KL. Basic structure-function relations of the epicardial pectoris: executive summary: the task force on the management of stable angina coronary vascular tree. Basis of quantitative coronary arteriography for diffuse pectoris of the European Society of Cardiology. Eur Heart J 2006;27:1341e81.
coronary artery disease. Circulation 1992;85:1987e2003.
Seiler C, Pohl T, Wustmann K, et al. Promotion of collateral growth by granulocyte- Windecker S, Allemann Y, Billinger M, et al. Effect of endurance training on coronary macrophage colony-stimulating factor in patients with coronary artery disease: artery size and function in healthy men: an invasive followup study. Am J Physiol Heart a randomized, double-blind, placebo-controlled study. Circulation 2001;104:2012e17.
Heart 2010;96:202e207. doi:10.1136/hrt.2009.184507


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