DUBAI20th APRIL 2012

ACE Inhibitors, the Cardioprotection Society

woRkshoP

Post Congress Report

Drawn from the speeches by

Samir ArnaoutAssociate Professor of MedicineAmerican University of Beirut-Medical CenterDepartment of Internal MedicineDivision of Cardiology

Claudio BorghiDepartment of Medicine, Aging and Clinical NephrologyUniversity of BolognaBologna, Italy

Athanasios J. ManolisDirector of Cardiology Department, Asklepeion HospitalAthens, Greece

Supported bythe Menarini group

Held during theWorld Congress of Cardiology, Dubai18-21 April 2012

CHAIRMAN: Samir Arnaout

ACE Inhibitors, the Cardioprotection Society

woRkshoP20th APRIL 2012

DUBAI

The world Congress of Cardiology, attended this year by ap-proximately 10,700 participants from all over the world, was held from April 18th to 21st, in Dubai (UAE). During the con-gress, on April 20th, an international satellite symposium on ACE-Inhibitors was sponsored by the Menarini Group.Prof. samir Arnaout (Beirut, Lebanon), president of the Leba-nese society of Cardiology, chaired the symposium, which featured prominent international speakers such as Profes-sors Athanasios Manolis (Athens, Greece) and Claudio Borghi (Bologna, Italy).The symposium started with a lecture by Prof. Manolis, who clearly explained the rationale for using ACE-inhibitors in the setting of antihypertensive treatment and cardiovascu-lar prevention, providing a comprehensive overview of the advantages of ACE inhibitors over other antihypertensive agents with respect to protection from target organ damage and progression of cardiovascular disease both in hyperten-sive and normotensive high-risk patients.

During the second lecture, Prof. Borghi summarized 20 years of research findings from the survival of Myocardial Infarction Long-term Evaluation (sMILE) program, aimed at specifically investigating the clinical efficacy of Zofenopril in patients with coronary artery disease (CAD). The sMILE project, which is still ongoing, has consistently demonstrated that Zofeno-pril exhibits a broad spectrum of cardioprotective effects both in the general CAD population and in several subgroups of patients.of note, the conference room was filled to capacity with over 600 participants: despite ACE inhibitors have been widely used for more than 20 years in the field of cardiovascular disease, the interest around these agents and particularly Zofenopril is still considerably high, as also reflected by a large number of recent trials (e.g. the sMILE IV and sMILE oVERALL trials) designed to confirm and further elucidate the mechanisms underlying the pleiotropic properties of ACE-inhibitors.

ACE Inhibitors, the Cardioprotection Society

woRkshoP20th APRIL 2012

PosT ConGREss REPoRT

ACE Inhibitors for the management of hypertensive patients with advanced cardiovascular risk

Athanasios J. Manolis

Zofenopril vs Amlodipine

Zofenopril 30-60 mg/day Amlodipine 5-10 mg/daySBP DBP

mm

Hg

Adapted from Farsang C, et al., Blood Pressure Suppl 2007;2:19-24

SBP DBP 0

-5

-10

-15

-20

SBP, systolic blood pressureDBP, diastolic blood pressure

Figure 1. Systolic and diastolic blood pressure decrements obtained after 12 weeks of treatment with Zofenopril 30-60 mg/d and amlodipine 5-10 mg/d in 303 patients with mild to moderate essential hypertension. SBP, systolic blood pressure; DBP, diastolic blood pressure. Parallel-group double-blind randomized multi-centre study.

Cardiovascular disease (CVD) should be seen as a progressive continuum, during which CV risk factors lead to subclinical organ damage and subsequent clinical disease, eventually re-sulting in CV events (e.g. stroke, myocardial infarction, heart failure) and death. In this light, CV risk factors such as hyper-tension should be promptly and effectively treated not only to lower blood pressure, but also to prevent target organ dam-age and overt CVD. Many effective antihypertensive agents are currently available, but not all of them provide the same

benefits in terms of cardioprotection. Angiotensin converting enzyme inhibitors (ACE-Is) are effective BP lowering drugs, even when compared with the widely used calcium channel blocker amlodipine (Fig. 1). The BP lowering efficacy of ACE-Is depends on blockade of the renin–angiotensin system (RAs), which plays a key role in the regulation of BP as well as CV and renal function. Chronic activation of the RAs is a major con-tributor to the pathogenesis of many CV and renal diseases.

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1-year Survival in AMI Patients Treated with Zofenopril or Placebo: Role of History of HBP

History of hypertension No history of hypertension

Adapted from Borghi C, et al. Am J Hypertens. 1999;12:665-72

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PlaceboZofenopril

RR= 39.3%p=0.041

RR= 23.4%p=0.22

Sur

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Sur

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Figure 2. Cumulative survival during 1 year in 565 hypertensive and 876 normotensive patients with acute anterior myocardial infarction treated for 6 weeks with Zofenopril (started at a dose of 7.5 mg/d and progressively uptitrated to a target dose of 30 mg bid) or placebo.

Furthermore ACE-Is, and Zofenopril in particular, provide specific BP-independent benefits in a broad range of CVD pa-tients including those with, or at risk for developing, diabetes mellitus. Thanks to their efficacy and protective effects, the European society of hypertension/European society of Car-diology (Esh/EsC) guidelines recommend the association of a RAs-blocking drug with either a diuretic or a calcium chan-nel blocker as a preferred combination therapy in patients who need more than one antihypertensive agent to control BP. of note, this recommendation was based on a large body of evidence mainly coming from trials on ACE-Is. As an exam-ple, in patients with acute myocardial infarction (AMI), ACE-I

treatment has consistently been shown to prevent the onset and progression of left ventricular (LV) dysfunction, and to improve in-hospital and long-term survival. Among patients with AMI, those with a history of hypertension, which greatly impacts on survival in such patients, may particularly benefit from ACE-I treatment: as compared with placebo, treatment with Zofenopril was shown to significantly reduce the 1-year risk of death by ≈ 40% in hypertensive AMI patients, and to lead to survival rates similar to those observed in normoten-sives, markedly decreasing the excess risk due to hyperten-sion (Fig. 2).

ACE Inhibitors for the management of hypertensive patients with advanced cardiovascular risk

Athanasios J. Manolis

Figure 3. The pharmacological characteristics of Zofenopril translate into a broad spectrum of beneficial effects. ED, endothelial dysfunction; NO, nitric oxide.

several experimental and clinical studies have demonstrated that the cardioprotective properties of Zofenopril are not only related to BP lowering, but also to ancillary properties that depend on its unique pharmacological profile and dif-ferentiate Zofenopril from other ACE-Is (Fig. 3). Zofenopril is a prodrug which is rapidly activated in tissues, opposite to other prodrugs with ACE inhibitory properties that are acti-vated only in serum and kidney. The long-lasting inhibition of heart ACE is determined by the high efficiency with which Zofenopril is uptaken by myocardial tissue and promptly con-verted to the active inhibitor zofenoprilat. Both Zofenopril and zofenoprilat are highly lipophilic, a characteristic that

enhances tissue and cell penetration, further increasing ef-ficacy and duration of action both at myocardial and vascular level. The high lipophilicity, along with the presence of a sulf-hydryl (sh) group, has also been postulated to be responsible for the protective action exerted by Zofenopril on pancreatic β-cells in vitro. Accordingly, experimental data indicate that Zofenopril may delay the onset of diabetes, an effect that was not observed with the non-sh ACE-I enalapril. Finally, the sh group confers Zofenopril free radical scavenging and remark-able anti-oxidant properties that translate into important anti-inflammatory and endothelium-protective effects via increased nitric oxide (no) availability.

ACE Inhibitors for the management of hypertensive patients with advanced cardiovascular risk

Athanasios J. Manolis

Zofenopril: Advantages of a Third Generation ACE-I

Zofenopril

- Free radical scavenging- Oxidative stress reduction- Prevention of ED- Anti-ischaemic effects- Anti-inflammatory effects- Anti-atherogenic effects- Reversal of apoptosis- Increase of NO

- Long duration of action- Effective in patients with renal and hepatic impairment

Prodrug SH Group High Lipophilicity

- High myocardial and vascular uptake- High tissue ACE blockade - Increased coronary flow- Reduced cellular hypertrophy

Figure 4. Effects of 12 week treatment with Zofenopril 15-30 mg/d or enalapril 20 mg/d on LDL oxidizability measured as LDL-associated MDA production (top) and systemic oxidative stress assessed by 8-isoPGF2 production (bottom). LDL, low density lipoprotein MDA, malondialdehyde, a marker of LDL oxidation.

Endothelial dysfunction is a hallmark, as well as an early pre-dictor, of several CVD, and as such represents an important therapeutic target for preventing or delaying the onset and progression of diseases such as hypertension, atherosclero-sis, heart failure and MI. In animal models Zofenopril has been shown to reduce atherosclerotic lesions and intima/media thickness, and to reverse vascular and cardiac remodelling. Clinical data confirm these experimental observations: in a study comparing the effect of Zofenopril and the beta-blocker atenolol in patients with essential hypertension, Zofenopril in-duced a significant improvement in endothelium-dependent vasodilation and oxidative stress, whereas no such change was observed with atenolol. Another study in a similar patient population showed that Zofenopril, but not enalapril, was able to decrease LDL peroxidation and systemic oxidative

stress despite similar BP reductions (Fig. 4). These findings strengthen the concept that not all ACE-Is share the same properties, and Zofenopril treatment may provide clinically relevant benefits beyond BP lowering. In summary, ACE-I treatment should be considered as first-choice therapy in patients with hypertension, as well as in several patient populations at high risk for CV events. how-ever, not all ACE-Is are equally effective for all indications, and only ACE-Is whose efficacy has been demonstrated should be used in specific clinical settings. The pharmacological char-acteristics of Zofenopril, a prodrug with a sh group and high lipophylicity, make this agent an excellent treatment option both for preventing and treating CVD at different stages of the CV continuum, in a broad spectrum of clinical settings.

ACE Inhibitors for the management of hypertensive patients with advanced cardiovascular risk

Athanasios J. Manolis

Effects of Zofenopril and Enalapril on LDL Oxidizability

Healthysubjects

(n= 46)

Adapted from Napoli C, et al. Am Heart J 2004;148:e5

MD

A(n

mol

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t)

0 5

1015202530 *

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4060

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*

Hypertensivepatients at baseline(n= 96)

Hypertensivepatients after

Zofenopril(n= 48)

Hypertensivepatients after

Enalapril(n= 48)

* p <0.05 or less vs healthy subjects

** p <0.05 or less vs hypertensive patients at baseline

Claudio Borghi

Sequence of events leading to CV diseases

RAS

RAS

RAS

RAS

RAS

RAS

RAS

RAS

Figure 1. Activation of the renin-angiotensin system (RAS) is involved in each step of the cascade of events leading to the onset and progression of CVD.

ACE-I treatment constitutes a physiological therapeutic ap-proach aimed at counteracting the hyperactivation of the RAs, which has been described at each stage of the chain of events starting from CV risk factors and progressively leading to structural and functional alterations eventually resulting in CVD and death (Fig. 1). The remarkable cardioprotective ef-fects of ACE-Is have been clearly demonstrated in many differ-ent trials showing that ACE-I treatment may improve clinical outcomes and prognosis in patients with and without coronary artery disease (CAD). with regard to Zofenopril, the cardiopro-tective role of this ACE-I has been clearly defined by the sur-vival of Myocardial Infarction Long-Term Evaluation (sMILE) program, a 20-year research project that assessed the effects

of Zofenopril in a large number of patients with CAD. The sMILE “main” trial, which was carried out in 1,556 AMI patients who were not undergoing thrombolysis, showed that Zofenopril treatment, started within 24 hours after onset of symptoms and continued for 6 weeks, significantly reduced both short-term and long-term mortality and the incidence of congestive heart failure (ChF), as compared with placebo. of note, ben-efits were evident early after (24-48 hours) onset of treat-ment. A comparison with other ACE-Is tested in similar patient populations showed a strict correlation between the reduction in mortality rate during the first 24 hours after AMI and the ex-tent of cardiac ACE inhibition, which was definitely greater for Zofenopril as compared with captopril and lisinopril.

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Zofenopril: Cardioprotection with a SMILE

Effects of ACEI in presence or absence of ASA in large RCT of patients with CHD or LVD

RR

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SOLVD-Treatment SOLVD-Prevention HOPE SMILE-1

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ACE-IACEI+ASA

Adapted from: Cleland JG et al, Curr Opin Nephrol Hyperten 2001;10:625-31 and Ambrosioni E et al, NEJM 1995;332:80-5

Enalapril Enalapril Ramipril Zofenopril P<0.001 P=0.057 P<0.007 P=NS

Figure 2. Clinical efficacy of different ACE-Is co-administered with acetyl salicylic acid (ASA) in the Studies of Left Ventricular Dysfunction (SOLVD), Heart Outcomes Prevention Evaluation (HOPE) and SMILE-1 studies. The effect of Zofenopril is not influenced by concomitant administration of ASA.

subanalyses of the sMILE trial confirmed the effects of Zofenopril treatment in many different subgroups of high-risk patients, i.e. patients with history of hypertension, metabolic syndrome, diabetes and dyslipidaemia. In these patients a striking benefit in terms of reduction of morbidity and mortal-ity was evident, possibly due to the antioxidant properties of Zofenopril, as well as its ability to downregulate the activity of the RAs, which is associated with hyperinsulinaemia, high levels of cholesterol ad progression of CVD in dysmetabolic patients. Furthermore, the sMILE-IsChEMIA study showed a reduction in the rate of major CV events and ischaemic events in patients with CAD and preserved LV function treated with Zofenopril, suggesting that this unique ACE-I has a primary anti-ischaemic effect. This finding may have important clinical implications since the reduction of major CV events in terms of

mortality and morbidity was strictly correlated with the anti-ischaemic effect of Zofenopril, independently of its BP lower-ing effect. Despite the solid evidence in favour of ACE-I treat-ment in CVD patients, some issues are still matter of debate. In fact, it has been suggested that clinical efficacy of ACE-Is can be reduced by concomitant administration of one of the most widely used therapeutic agents in CV medicine, i.e. aspi-rin (acetyl salicylic acid, AsA). This issue was emphasized both by the AhA/ACC and the EsC guidelines on the management of hF, which state that there is evidence supporting an inter-action between aspirin and ACE-I treatment. nevertheless, al-though the clinical efficacy of the ACE-Is enalapril and ramipril has been shown to be significantly reduced when these drugs are co-administered with AsA, in the sMILE trial this was not true for Zofenopril (Fig. 2).

Claudio Borghi

Zofenopril: Cardioprotection with a SMILE

Primary end-point :One year CV mortality and one year hospitalization for CV causes

Cum

Haz

ard

Log Rank test, p < 0.05

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RR (95% CI)= 0.70(0.52-0.96)

Adjusted P=0.028

zofrenoprilramiprilzofrenopril-censoredramipril-censored

Treatment

Borghi C, et al. J. Am. Coll. Cardiol., April 5, 2011; 57: E300 (abstract)

Figure 3. 1-year mortality and CV hospitalisation in patients treated with ASA 100 mg/d plus Zofenopril 30-60 mg/d (n=360) or ramipril 5-10 mg/d (n = 368) in the SMILE-4, a double-blind, randomised study.

The observation that, opposite to other ACE-Is, the clinical ef-ficacy of Zofenopril was not influenced by concomitant admin-istration of AsA suggests that there is actually an interaction between ACE-Is and AsA, but such interaction depends on the ACE-I used. Based on these premises, the sMILE-4 study was designed to assess the 1-year combined occurrence of death, CV hospitalization and deterioration of LV function in 768 pa-tients with post-MI LV dysfunction who were treated either with Zofenopril or ramipril, both in combination with AsA. Re-sults of the sMILE-4 demonstrate that the risk for mortality and CV hospitalization in patients treated with Zofenopril plus AsA was significantly lower than that in patients treated with ramipril (Fig. 3). The analysis of different confounding vari-ables (e.g. BP control, concomitant medications) did not show

any significant differences between Zofenopril and ramipril, meaning that the greater clinical efficacy of Zofenopril relies upon differences in the pharmacological profile of the two drugs. The ancillary anti-ischaemic and anti-oxidative prop-erties of Zofenopril may possibly account for the better out-comes reported in Zofenopril treated patients. Furthermore, thanks to the presence of a sh group, Zofenopril has been shown to increase no availability, which may potentiate the inhibition of platelet aggregation by AsA and counteract the negative effects (i.e. vasoconstriction) of this agent. Finally, the effect of Zofenopril may be less affected by concomitant administration of AsA because of the lesser interaction with the bradykinin system as compared with other ACE-Is.

Claudio Borghi

Zofenopril: Cardioprotection with a SMILE

1-year event-free survival and hospitalization in the SMILE-OVERALL study

Borghi C et al J. Am. Coll. Cardiol., 2012; 59: E454 (abstract)

Survival and hospitalization

*Lisinopril, Ramipril**Adjusted for HBP, previous MI, LVEF

Others vs. placebo*OR=0.74 (0.54-0.99)

p=0.005

Sur

viva

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Zofenopril vs others*OR=0.57 (0.44-0.75)

p=0.0001**

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Zofenopril vs. placeboOR=0.36 (0.29-0.47)

p=0.0001

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n. 3630

Cox Regression model, p-value <0.001 Treatmentplacebo

others

zofenopril

Figure 4. 1-year survival and hospitalization in the SMILE-OVERALL study, which cumulatively examined the results of SMILE 1-4 studies (n=3,630) to determine the impact of Zofenopril on 1-year CV mortality and morbidity vs. placebo or active controls (lisinopril, ramipril).

Recently, the cumulative efficacy of Zofenopril in 3,630 pa-tients with CAD enrolled over 15 years of the sMILE project was reviewed in the sMILE-oVERALL analysis, which com-pared the effect of Zofenopril, other ACE-Is (lisinopril, rami-pril) and placebo with respect to CV mortality and morbidity. As shown above, the occurrence of mortality and morbidity was significantly reduced in patients treated with Zofenopril both versus placebo and other ACE-Is, mainly due to a lower rate of hospital admission (Fig. 4). Furthermore, the event-free survival time was significantly increased in patients treated with Zofenopril as compared with other ACE-Is. Results of the sMILE-oVERALL analysis confirm the favourable effects of Zofenopril treatment in patients with CAD. The greater reduc-tion in mortality and morbidity observed with Zofenopril in

comparison to placebo and other ACE-Is further supports a difference in the efficacy of various ACE-Is, which is likely due to both the ACE-inhibitory properties and the pharmacologi-cal profile of Zofenopril. In fact, compelling evidence suggests that the cardioprotective effects of Zofenopril are not related to just one specific mechanism of action, they rather depend on the different characteristics of the drug (high lipophilicity, sh group, inhibition of ACE). These peculiar characteristics account for a wide spectrum of efficacy both in the general MI population and in several subgroups of high-risk patients (e.g. patients with hypertension, diabetes, metabolic syndrome, hypercholesterolemia) in whom Zofenopril treatment could largely contribute to an improvement of clinical outcome.

Claudio Borghi

Zofenopril: Cardioprotection with a SMILE

ACE Inhibitors, the Cardioprotection Society

woRkshoP20th APRIL 2012

PosT ConGREss REPoRT

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