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Transcript of journal club Preventing Left Ventricular Hypertrophy By ACE Inhibition In
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Preventing Left Ventricular HypertrophyPreventing Left Ventricular HypertrophyBy ACE Inhibition In HypertensiveBy ACE Inhibition In HypertensivePatients With Type 2 DiabetesPatients With Type 2 Diabetes
Piero Ruggenenti, MDIlian Iliev, MD
Grazia Maria Costa, MDAneliya Parvanova, MD
Annalisa Perna, STAT SCI DGiovanni Antonio Giuliano, DIPL STAT
Nicola Motterlini, STAT SCI DBogdan Ene-Iordache, ENG DGiuseppe Remuzzi, MD, FRCPthe BENEDICT Study Group
Diabetes Care31:1629-1634 Aug 2008
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INTRODUCTION
In patients with type 2 diabetes, leftventricular hypertrophy (LVH) predictscardiovascular events, and the prevention
of LVH is cardioprotective.
Antihypertensive therapy may effectivelylimit the incidence of ECG-LVH, regardless
of the treatments used to reduce bloodpressure
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However, HOPE &LIFE trials showedthat, in patients with ECG-LVH atinclusion, the ACE inhibitor ramipril
and the angiotensin receptor blockerlosartan, respectively, regressed LVHmore effectively than drugs that donot directly interfere with the renin-
angiotensin-aldosterone system .
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These trials had there limitations totest whether RAAS inhibitor therapy
may also prevent new-onset LVH insubjects with normal left ventricularmass to start with is unknown.
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OBJECTIVE
1. To compare the effect of ACE
versus non-ACE inhibitor therapy onincident electrocardiographic (ECG)evidence of left ventricularhypertrophy .
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OBJECTIVE
2. Evaluation of the relationships
between incidence of ECG-LVH andbaseline and follow-up variables,including treatable risk factors suchas blood pressure and A1C.
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RESEARCH DESIGN AND METHODS
Patients
hypertensive type 2 diabetic patients
from the Bergamo Nephrologic DiabetesComplications Trial (BENEDICT)
who had no ECG-LVH at inclusion.
Sample Size400 patients per group
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Randomly assigned to at least 3years of blinded ACE inhibition withtrandolapril (2 mg/day) or to non-
ACE inhibitor therapy.
Treatment was titrated to
systolic/diastolic blood pressure
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ECG-LVH and other outcome variables:
Standard 12-lead ECGs were recordedat 25 mm/s and 1 mV/cm calibration atbaseline and every year thereafter.
They were centrally and independently
evaluated by two investigators whowere blinded to treatment allocation andpatient data.
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ECGs with inconsistent readingsevaluated by a third independent
cardiologist
Systolic and diastolic blood pressuremeasured in the morning before
treatment administration
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Data Report
in dedicated case report formsdoubly entered in an ad hoc database
that was eventually merged with theBENEDICT database.
Data Monitoringby the Monitoring Unit of the Clinical
Research Center for Rare Diseases Aldo& Cele Dacc of the Mario NegriInstitute for Pharmacological Research.
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Statistical analysesby the Laboratory of Biostatistics of the
Clinical Research Center.
Between-group comparisons
by unpaired t test or Wilcoxon's rank-sumtest
by a CHI SQUARE test or Fisher's exact test.
Within-group comparisons by paired t test or Wilcoxon's signed-rank
test
by the McNemar test.
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Main study resultsreported by a Cox regression model.
Graphic representationKaplan-Meier curves were plotted foreach group considered.
P< 0.05 was considered statisticallysignificant.
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RESULT
Of 905 patients with readable ECG atbaseline and at least 1 year offollow-up, 816 (433 receiving ACEand 383 receiving non-ACE inhibitortherapy) had no ECG evidence of
LVH.
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Table 1Table 1
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Figure 1- Kaplan-Meier curves for the percentages of subjects receiving ACE therapy withtrandolapril(ACEi YES) or receiving non-ACE inhibitor therapy(ACEi NO) who developed ECG-LVH
adjusted for prespecified baseline covariates was significant(P=0.0018)
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Table 2Table 2
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Table 3Table 3
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Blood Pressure & Metabolic Control
Follow-up systolic and diastolic bloodpressure was lower in the ACE than inthe non-ACE inhibitor group.
Follow-up A1C levels were lower in theACE than in the non-ACE inhibitorgroup.
Blood glucose was similar in the twotreatment groups.
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DISCUSSIONDISCUSSION
Both hemodynamic and
nonhemodynamic factors mostlikely contributed to thecardioprotective effect oftrandolapril therapy.
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It increases vessel wall compliance and reduce
arterial wave reflection amplitude15
thus reduce aortic and left ventricular bloodpressure even more consistently thanperipheral artery blood pressure.15
Comparable peripheral blood pressure, ACEinhibitors may reduce central pressures andleft ventricular afterload more effectively thanother antihypertensive drugs.16
15 Mitchell GF,Pfeffer MA,Finn PV,Pfeffer JM:Equipotent antihypertensive agents variously affect pulsatile hemodynamics and regression ofcardiac hypertrophy in spontaneously hypertensive rats Circulation 94:2923-2929,1996
16 Topouchian J, Asmar R, Sayegh F, Rudnicki A, Benetos A, Bacri AM, Safar ME: Changes in arterial structure and function under trandolapril-verapamil combination in hypertension. Stroke 30:10561064, 1999
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Through direct inhibition of cardiac
RAASAngiotensin II promotes the growth of
myocytes independently of loading
conditions
17
, and ACE inhibitors mayprevent the hypertrophic effect ofangiotensin II even at doses that do not
affect the blood pressure14
17 Aceto JF, Baker KM: [Sar1]angiotensin II receptor-mediated stimulation of protein synthesis in chick heart cells. Am J Physiol 258:H806813, 1990
14 Linz W, Schaper J, Wiemer G, Albus U, Scholkens BA: Ramipril prevents left ventricular hypertrophy with myocardial fibrosis without blood pressurereduction: a one year study in rats. Br J Pharmacol
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Increases local bradykininbioavailability through inhibition ofthe myocardial kallikrein-kinin
pathway
Thus may directly prevent myocardialhypertrophy 23
23 Crowley SD, Gurley SB, Herrera MJ, Ruiz P, Griffiths R, Kumar AP, Kim HS, Smithies O, Le TH, Coffman TM: Angiotensin II causes hypertension andcardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci USA 103:1798517990, 2006
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ACE inhibitors also amelioratearterial compliance25
In patients with type 2 diabetesVascular stiffness and RAASactivation is common24.
25 Safar ME, Laurent SL, Bouthier JD, London GM, Mimran AR: Effect of converting enzyme inhibitors on hypertensive large arteries in humans. JHypertens Suppl 4:S285S289, 1986
24 Giacchetti G, Sechi LA, Rilli S, Carey RM: The renin-angiotensin-aldosterone system, glucose metabolism and diabetes. Trends Endocrinol Metab16:120126, 2005
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Thus, the coexistence of severalabnormalities that can be ameliorated
by RAAS inhibitors also explain theremarkable protective effect oftrandolapril against ECG-LVH weobserved here6.
6 Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q, Bosch J, Sussex B, Probstfield J, Yusuf S: Reduction of cardiovascular risk by regression ofelectrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation 104:16151621, 2001
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CONCLUSIONCONCLUSION
ACE inhibition with trandolapril significantlyreduced the incidence of ECG-LVH in patientswith arterial hypertension and type 2 diabetescompared with non-ACE inhibitor therapy.
The protective effect of trandolapril against ECG-LVH was already evident at 1 year after randomassignment and progressively increased onfollow-up.
Sokolow-Lyon and Cornell voltages consistentlydecreased with trandolapril therapy, whereasthey did not change appreciably with non-ACEinhibitor therapy.
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STRENGTHSTRENGTH
Hypertension along with type 2 diabetesoccurs widely thus large number ofpopulation could be be benefited from theresult of the study.
Large sample size was taken sointerpretation of data is more accurate.
Randomised double blind parallel groupstudy.
As per the CONSORT 2010 guidelinesresults were reported with definite values.
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LIMITATIONSLIMITATIONS
LVH assessed by electrocardiography.ECG may underestimate LVH in obese
subjects.
The study gave no reasons why theresults were reported at one year intervalwhile the original study was planed for 3year duration.
t test were used in the statistical analysis
Participant flow description was not as perprotocol in CONSORT guidelines
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Bergamo Nephrologic Diabetes
Complications Trial
Was prospective, randomized,double-blind, parallel group study.
Evaluated the possibility ofpreventing the onset of persistent
microalbuminuria in patients withtype 2 diabetes and arterialhypertension
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randomly assigned to at least 3years of treatment with one of thefollowing study drugs:
a nondihydropyridine calciumchannel blocker
an ACE inhibitor
a fixed-dose combination placebo.
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HEART OUTCOME PREVENTIONEDUCATION
Randomized trial of the ACE inhibitorramipril and vitamin E in patients at highrisk for cardiovascular events versusplacebo.
Primary end point of the study wascomposite of myocardialinfarction,stroke, or death fromcardiovascular causes.
Ramipril significantly reduced the rates ofdeath, myocardial infarction, and strokein a broad range of high-risk patients
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LOSARTAN INTERVENTION FOR ENDPOINTLOSARTAN INTERVENTION FOR ENDPOINTREDUCTION IN HYPERTENSIONREDUCTION IN HYPERTENSION
Double-blind, randomized trial to compare theeffects of losartan and atenolol on cardiovascularmorbidity and mortality in high-risk patients withhypertension and left ventricular hypertrophy(LVH)
Losartan-based compared with atenolol-basedantihypertensive therapy was associated with: A reduction in the combined primary endpoint
of cardiovascular death, stroke or MI (-13%)
fewer strokes (-25%) similar blood pressure reduction
Losartan reduced the rate of new-onset diabetes(-25%)
Dahlof B, et al. Lancet. 2002;359:995-1003.
Lindholm LH, et al. Lancet. 2002;359:1004-1010. www.hypertensiononline.org