Differential Antiplatelet Effects

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D. SkowaschA. ViktorM. Schneider-SchmittB. LderitzG. Nickenig

G. Bauriedel

Differential antiplatelet effects

of angiotensin converting enzyme inhibitors

Comparison of ex vivo platelet aggregationin cardiovascular patients with ramipril, captopril

and enalapril

Clin Res Cardiol 95:212216 (2006)DOI 10.1007/s00392-006-0363-1

Received: 3 May 2005Accepted: 22 December 2005Published online: 17 February 2006

Dr. Dirk Skowasch ()) Achim ViktorMelanie Schneider-SchmittProf. Dr. Dr. h.c. Berndt LderitzProf. Dr. Georg NickenigProf. Dr. Gerhard BauriedelDepartment of Internal Medicine IICardiologyHeart Center University of BonnSigmund-Freud-Str. 2553105 Bonn, GermanyE-Mail: [email protected]

ORIGINAL PAPER

n Summary Background Increas-ing evidence suggests that angio-tensin converting enzyme (ACE)

inhibitors exert antithromboticeffects. Based on the assumption ofdifferential effects of various ACEinhibitors on coagulation, the aimof the present study was to evalu-ate the coagulative activities ofcardiovascular (CV) patientstreated with either ramipril, cap-topril, and enalapril, and to com-pare these with patients treatedwith established antithromboticssuch as aspirin (ASA) and clopi-dogrel or none of these medica-tion. Methods Blood samples of320 CV patients with coronary ar-tery disease and/or arterial hyper-tension were analyzed by whole-blood aggregometry. Platelet ag-gregation was determined bymeasuring the increase in impe-dance across paired electrodes inresponse to the aggregatory agentscollagen and adenosine dipho-sphate (ADP), respectively. Thesedata were correlated with medicaltreatment. Results Platelet aggre-

gation was attenuated ex vivo byramipril and captopril as well asby ASA and clopidogrel. While

collagen-induced platelet aggrega-tion was significantly reduced byramipril (35%; P


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Artery disease (EUROPA) demonstrated a 20% rela-tive reduction in the combined primary endpointcardiovascular mortality, non-fatal myocardial in-farction, and resuscitated cardiac arrest [3]. Recently,we and others demonstrated attenuated platelet ag-gregation with ACE inhibitor therapy, which might at least partly explain the pleiotropic beneficial ef-

fects of this drug class on cardiovascular events [1,13]. Since individual ACE inhibitors differ substan-tially in their physiochemical properties, enzyme-binding kinetics, pharmacokinetic profile, organspecific affinity and selectivity, the purpose of thepresent study was to evaluate different ACE inhibi-tors versus aspirin and clopidogrel as classical an-tithrombotics in their effect on platelet aggregation,by use of whole-blood aggregometry in patients withcardiovascular disease.

MethodsWe prospectively enrolled 320 stable cardiovascularpatients, between February 2000 and February 2003.These patients were recruited from consecutive pa-tients who presented at our Heart Center. All partici-pants gave informed consent before enrollment. In-clusion criteria were coronary artery disease, arterialhypertension, or both [1]. Treatment with glycopro-tein II b/IIIa receptor blockers, aspirin as analgesictherapy within the last four weeks, angiotensin IItype 1 receptor antagonists or combined antithrom-botic/ACE inhibitor medication led to study exclu-sion. At the baseline study visit, detailed demo-graphic data and a background medication profilewere collected (Table 1). Patients were classified intofive groups of study participants: group A, patientswith cardiovascular disease who were not takingACE inhibitors or antithrombotic medication (con-trol group); group B, patients taking aspirin (100 to300 mg/d) and/or clopidogrel (75 mg/d); group C,patients taking ramipril; group D, patients takingcaptopril; group E, patients taking enalapril. Of thepatients with ACE inhibitor medication, 21 weretreated with ramipril (2.510 mg/d, mean 5.5 3.0 mg/d), 33 were treated with captopril (6.25-150mg/d; mean 45.323.4 mg/d) and 25 with enalapril(2.5-20 mg/d; mean 9.66.2 mg/d); patients receivedACE inhibitors for a minimum of 2 weeks.

After recruitment of the patients, venous bloodsamples were collected in plastic tubes containing a1:10 volume of acid citrate anticoagulant (2 parts of0.1 mol/l citic acid to 3 parts of 0.1 mol/l trisodiumcitrate) and subsequently (between 30 min and 5 h)processed, as recently described [1]. Platelet aggrega-tion in whole blood samples were examined by an

impedance aggregometer (Model 560, Chrono-Log,Havertown, PA, USA). Measurements were per-formed at 37 8C and a stirring speed of 900 rpm. Ac-cording to the recommendations of the manufac-turer, citrate blood (500 ll) was diluted 1-to-1 with0.9% NaCl and prewarmed for 5 min at 37 8C. Afterthe electrode was placed, aggregation was induced

by the stimulatory agents collagen (final concentra-tion 2 lg/ml) and adenosine diphosphate (ADP; fi-nal concentration 5 lmol/ml). Collagen and ADPwere purchased from Nobis (Endingen, Germany).Platelet aggregation was monitored continually for6 min, and responses were recorded as electrical im-pedance across paired electrodes (in Ohm). Inhibi-tion of aggregation was evaluated as the percentagecomparing the extent of aggregation in the presence(groups B-E) or absence (group A) of the antiaggre-gatory regimens studied.

Baseline demographics, use of medication, anddata of whole-blood aggregometry were compared.

Group comparisons were performed by one-wayanalysis of variance (ANOVA) with a Bonferroni posthoc test. P values


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by 47% by clopidogrel monotherapy (n= 12;P = 0.19). After ADP induction, platelet aggregationwas reduced by 22% with aspirin (P=0.01) and by72% with clopidogrel (P=0.02).

Discussion

Beyond confirming the antiaggregatory effects of theestablished antithrombotics aspirin and clopidogrel,the present study shows that ACE inhibitors attenu-

214 Clinical Research in Cardiology, Volume 95, Number 4 (2006) Steinkopff Verlag 2006

Table 1 Baseline characteristics of patients

Group A B C D E

No. 151 90 21 33 25Age (yr) 61 16 63 12 67 10 65 9 68 11Male sex 70 (46) 45 (50) 8 (38) 12 (36) 14 (56)CAD 71 (47) 58 (64) 11 (52) 15 (44) 18 (72)Previous MI 21 (24) 19 (21) 5 (24) 7 (21) 7 (21)

Hypertension 90 (60) 58 (64) 14 (67) 19 (58) 18 (72)Systolic BP (mmHg) 139 16 138 15 143 19 141 17 141 18Diastolic BP (mmHg) 80 10 79 11 83 9 81 12 81 10

Other risk factorsDiabetes 17 (11) 21 (23) 7 (33) 5 (15) 8 (32)Hyperlipidemia 73 (48) 55 (61) 12 (57) 16 (48) 16 (60)Current smoker 50 (33) 38 (42) 6 (29) 10 (30) 11 (44)Familial disposition 38 (25) 25 (28) 5 (24) 13 (39) 5 (20)Obesity 31 (21) 17 (21) 5 (24) 4 (12) 5 (20)

MedicationAspirin/clopidogrel 0 90 (100) 0 0 0ACE inhibitors 0 0 21 (100) 33 (100) 25 (100)Nitrates 40 (26) 27 (30) 9 (43) 10 (30) 10 (40)b-blockers 62 (41) 46 (51) 11 (52) 14 (42) 14 (56)Calcium channel bl. 22 (15) 15 (17) 4 (19) 6 (18) 4 (16)

Statins 42 (28) 41 (46) 10 (48) 11 (33) 10 (40)

Baseline characteristics [number of patients (%) or meanSD]. A cardiovascular patients without ACE inhibitors or antithrombotic medication; B patients withaspirin/clopidogrel; C patients with ramipril; D patients with captopril; E patients with enalapril; ACE angiotensin converting enzyme; CAD coronary arterydisease; MI myocardial infarction

Fig. 1 Influence of established antithrombotics and angiotensin-converting

enzyme (ACE) inhibitors on platelet aggregation. Impedance changes in Ohmafter induction with collagen (a) or with adenosine diphosphate (b) in pa-

tients not receiving antithrombocyte or ACE inhibitor medication (group A),

in patients receiving aspirin/clopidogrel (group B), and in participants receiv-ing ramipril (C), captopril (D) or enalapril (E). n.s. not significant

a b


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ate platelet aggregation and thereby demonstrates adifferential antiaggregatory profile of different ACEinhibitors. While ramipril and captopril therapy re-duced ex vivo platelet aggregation, no antithrombot-ic effect was seen with enalapril. The underlyingmechanisms remain unclear so far. It has been hy-pothesized that tissue affinity might be responsible

for some of the beneficial cardiovascular propertiesof ACE inhibitors. However, the present findingssuggest that tissue ACE inhibitor affinity does notaffect the antithrombotic effects of ACE inhibitors,since ramipril is a tissue-ACE inhibitor, and capto-pril and enalapril are non-tissue-ACE inhibitors.Likewise, others have not found a correlation be-tween tissue-ACE affinity and risk of myocardial in-farction in patients with arterial hypertension [12].Possible mechanisms for reduced platelet aggrega-tion with ACE inhibitor therapy are decreased tissuefactor expression with ACE inhibition [20], loweredconcentrations of circulating tissue factor [10], and

reduced vascular [5] and systemic inflammation [9].At first glance, parallel implications may resultfrom the present ex vivo study and recent data fromHOPE [17] and other trials [68, 11, 15, 16, 19]. TheHOPE trial tested ramipril in patients with athero-sclerosis in the absence of heart failure or left-ven-tricular dysfunction, and showed a significant de-crease in the combined end point of cardiovasculardeath, myocardial infarction, and stroke, but not inunstable angina with electrocardiographic changesor in hospitalization rate [17]. One may concludethat clinical end points caused by total thromboticvascular occlusion, but not those by incomplete cor-onary obliteration are significantly influenced. Be-yond normalization of endothelial dysfunction andplaque stabilization, which were both discussed asbeing responsible for the clinical benefit of ramipril[17], our results support the concept of an additionalantithrombotic effect of ramipril. Although it is un-clear whether the benefits of ramipril can be extra-polated to other ACE inhibitors, data from unse-lected patients of the prospective multicenter regis-try MITRA PLUS suggested that ramipril has morebeneficial effects on cardiovascular events than treat-ment with other ACE inhibitors [18]. The cardiopro-tective findings seen in HOPE and EUROPA do notnecessarily presume a cardiovascular class effect ofACE inhibitors. The Prevention of Events with An-

giotensin Converting Enyzme Inhibition (PEACE)trial failed to provide any further benefit in terms ofdeath from cardiovascular causes, myocardial infar-cion, or coronary revascularization among a largecohort of patients with stable coronary diseasetreated with the ACE inhibitor trandolapril [2].

To date, several well-controlled clinical trials in-

volving post-MI patients with left ventricular dys-function have been performed with the differentACE inhibitors studied in the present work. The re-duction in all-cause mortality observed in short-term trials (CCS-1 [8] and ISIS-4 [7] with captopril)has been very modest, and in the CONSENSUS IItrial there was even an increase in mortality withenalapril [15]. In long-term studies (SAVE [11] withcaptopril, AIRE [16] and AIREX [6] with ramipril),post-MI patients with left ventricular dysfunctionand/or clinical signs and symptoms of heart failurewere included and followed up for a longer period.The reduction in all-cause mortality observed in

these studies was even greater compared to that inthe short-term trials. One may speculate that anti-thrombotic effects of ramipril and captopril, as ob-served in the present study, were, at least in part, re-sponsible for these beneficial effects, whereas noantithrombotic effect was seen with enalapril in thepresent study, analogous to an increase in mortalityin the CONSENSUS II trial [15].

The concept of our present study was to screen theimpact on platelet aggregation brought in by basicdrug prescription in cardiovascular patients as seenin daily practice. Of course, there are several limita-tions of the study. No information can be drawn re-garding the clinical relevance of ACE inhibitor re-duced platelet aggregation. In remains open how longand in what dosage ACE inhibitors should be taken toachieve antithrombotic effects. In this study, medica-tion use was based on answers to questionnaires; druglevels or pill counts were not performed.

In summary, the present study demonstrates adifferential antiaggregatory profile among differentACE inhibitors, which may explain at least in partdifferent effects on cardiovascular events as observedin large clinical trials. Further head-to-head investi-gations with equivalent dosages of different ACE in-hibitors may be warranted in large-scale studies tofully elucidate clinical differences and similaritiesamong ACE inhibitors.

215D. Skowasch et al.Differential antiplatelet effects of ACE inhibitors


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216 Clinical Research in Cardiology, Volume 95, Number 4 (2006) Steinkopff Verlag 2006

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