Angiotensin-converting enzyme inhibitors (ACEIs) are currently recommended for managing arterial hypertension, the progression of chronic renal disease, post-myocardial infarction, congestive heart failure, and type 2 diabetes mellitus. |
In patients with acute or chronic coronary syndrome and heart failure ACEIs appear to provide several benefits beyond blood pressure control. |
Among the various drugs of this class, zofenopril, a lipophilic, sulfhydryl group-containing ACEI, seems to contribute to additional clinical benefits in some identifiable populations of subjects. |
The clinical efficacy and safety of zofenopril has been evaluated in more than 3,600 post-acute myocardial infarction patients with or without left ventricular dysfunction in the four randomized controlled trials of the SMILE program. |
The pharmacological characteristics and ancillary features of zofenopril with potent cardioprotective activity seem to differentiate it from other ACEIs and to confer further benefits to patients. |
Introduction
RAS Involvement in CVD
Role of ACEIs in CVD According to Current Guidelines
Drug | Molecular structure | Absorption (%) | Half-life (h) | Metabolism | Main route of elimination | Approved indications | Hypertension | Heart failure | ||
---|---|---|---|---|---|---|---|---|---|---|
Initial daily dose (mg) | Maximal daily dose (mg) | Initial daily dose (mg) | Initial daily dose (/mg) | |||||||
Benazepril | Dicarboxylic group | 37 | 10–11 | + (benazeprilat) | Renal | Hypertension | 10 | 40 | – | – |
Captopril | Sulfhydryl group | 60–75 | 2 | + | Renal | Hypertension, heart failure, post-AMI patients with LVD, type 1 diabetic nephropathy | 12.5 (tid) | 150 (tid) | 6.25 (tid) | 150 (tid) |
Cilazapril | Dicarboxylic group | 45–85 | 1.5–2.0 | + (cilazaprilat) | Renal | Hypertension and heart failure | 1–1.25 | 5 | 0.5 | 5 |
Enalapril | Dicarboxylic group | 60 | 11–14 | + (enalaprilat) | Renal | Hypertension and heart failure (or asymptomatic LVD) | 5 | 40 | 2.5 (bid) | 20 (bid) |
Fosinopril | Phosphonate group | 36 | 12 | + (fosinoprilat) | Renal and hepatic | Hypertension and heart failure | 10 | 40 | 5–10 | 40 |
Lisinopril | Dicarboxylic group | 25 | 12 | – | Renal | Hypertension, heart failure and post-AMI hemodynamically stable patients | 10 | 40 | 2.5–5 | 40 |
Moexipril | Dicarboxylic group | 13 | 2–9 | + (moexiprilat) | Renal | Hypertension | 7.5 | 30 | – | – |
Perindopril | Dicarboxylic group | 65–75 | 1.2 | + (perindoprilat) | Renal | Hypertension and stable CAD patients | 4 | 16 | – | – |
Quinapril | Dicarboxylic group | 50–80 | 2.3 | + (quinaprilat) | Renal | Hypertension and heart failure | 10–20 | 80 | 5 (bid) | 20 (bid) |
Ramipril | Dicarboxylic group | 50–60 | 13–17 | + (ramiprilat) | Renal | Hypertension, heart failure (post-AMI), high risk CV patients | 2.5 | 20 | 2.5 (bid) | 5 (bid) |
Trandolapril | Dicarboxylic group | 40–60 | 16–24 | + (trandolaprilat) | Hepatic | Hypertenion and post-AMI (CHF or asymptomatic LVD patients) | 1–2 | 4 | 1 | 4 |
Zofenopril | Sulfhydryl group | 78 | 5.5 | + (zofenoprilat) | Renal | Hypertension and post-AMI (< 24-h) | 15 | 60 | – | – |
Drug | Post-AMI | Other indication | ||
---|---|---|---|---|
Initial daily dose (mg) | Maximal daily dose (mg) | Initial daily dose (mg) | Maximal daily dose (mg) | |
Benazepril | – | – | – | – |
Captopril | 6.25 (tid) | 50 (tid) | – | 25 (tid) |
Cilazapril | – | – | – | – |
Enalapril | – | – | – | – |
Fosinopril | – | – | – | – |
Lisinopril | 5 | 10 | – | – |
Moexipril | – | – | – | – |
Perindopril | – | – | 4 | 8 |
Quinapril | – | – | – | – |
Ramipril | – | – | 2.5 | 10 |
Trandolapril | 1 | 4 | – | – |
Zofenopril | 7.5 (bid) | 30 (bid) | – | – |
Class of recommendation | Level of evidence | |
---|---|---|
Recommendations for treating arterial hypertension [10] | ||
Among all antihypertensive drugs, ACEIs, ARBs, BBs, CCBs, and diuretics (thiazides and thiazide-like drugs such as chlorthalidone and indapamide) have demonstrated effective reduction of BP and CV events in RCTs, and are thus indicated as the basis of antihypertensive treatment strategies | I | A |
Combination treatment is recommended for most hypertensive patients as initial therapy. Preferred combinations should comprise a RAS blocker (either an ACEI or an ARB) with a CCB or diuretic. Other combinations of the five major classes can be used | I | A |
It is recommended that if BP is not controlled with a two-drug combination, treatment should be increased to a three-drug combination, usually a RAS blocker with a CCB and a thiazide/thiazide-like diuretic, preferably as an SPC | I | A |
Recommendations for treating patients with symptomatic HF with reduced ejection fraction [15] | ||
An ACEI is recommended, in addition to a BB, for symptomatic patients with HFrEF to reduce the risk of HF hospitalization and death | I | A |
A BB is recommended, in addition to an ACEI, for patients with stable, symptomatic HFrEF to reduce the risk of HF hospitalization and death | I | A |
An MRA is recommended for patients with HFrEF who remain symptomatic despite treatment with an ACEI and a BB to reduce the risk of HF hospitalization and death | I | A |
Recommendations for treating chronic coronary syndrome [18] | ||
ACEIs (or ARBs) are recommended if a patient has other conditions (e.g., HF, hypertension, or diabetes) | I | A |
ACEIs should be considered in CCS patients at very high risk of CV events | IIa | A |
Recommendations for treating STEMI [22] | ||
ACEIs are recommended, starting within the first 24-h of STEMI in patients with evidence of HF, LVSD, diabetes, or anterior AMI | I | A |
An ARB, preferably valsartan, is an alternative to ACEIs in patients with HF and/or LVSD, particularly those who are intolerant to ACEIs | I | B |
ACEIs should be considered in all patients in the absence of contraindications | IIa | A |
Zofenopril: A Cardioprotective ACEI
Pharmacological properties | Clinical effects |
---|---|
Higher lipophilicity and tissue penetration | Effective prevention of CV events |
Higher affinity and more persistent binding to tissue ACE (cardiac, renal and vascular) | Effective prevention of CV events |
Lesser Bk-dependent effect | Good safety (reduced frequency of hypotension, cough, and renal function deterioration) |
Significant antioxidant effect | Significant anti-ischemic effect |
Increased release and availability of H2S | Improved CV function |
Study | Period of the enrolment | Inclusion criteria | Intervention (n) | Control (n) | Daily zofenopril dose | Control | Treatment duration (weeks) | Post treatment follow-up (weeks) |
---|---|---|---|---|---|---|---|---|
SMILE Pilot | 1988–1989 | AMI with lack of indication for a thrombolytic therapy | 101 | 103 | 15–30 mg | Placebo | 48 | – |
SMILE-1 | 1991–1992 | Anterior AMI not eligible for thrombolytic therapy in the previous 12 h | 772 | 784 | 15–60 mg | Placebo | 6 | 48 |
SMILE-2 | 1998–1999 | Thrombolytic treatment within 12 h from AMI and SBP > 100 mmHg | 504 | 520 | 15–60 mg | Lisinopril 2.5–10 mg daily | 6 | – |
SMILE-3 | 1998–2001 | AMI in the preceding 6 weeks with preserved left ventricular ejection fraction (> 40%), prior thrombolysis and treatment with ACEIs | 172 | 177 | 15–60 mg | Placebo | 24 | – |
SMILE-4 | 2005–2009 | AMI in the previous 24 h treated or untreated with PTCA, with clinical and/or echocardiographic evidence of left ventricular dysfunction | 365 | 351 | 15–60 mg plus ASA100 mg daily | Ramipril 10 mg daily plus ASA100 mg daily | 48 | – |
SMILE Overall | 1991–2009 | The same of the SMILE-1 to -4 study | 1808 | 1822 | 30–60 mg | Placebo, lisinopril or ramipril | 6–48 | – |
Study | Primary end-point | Main results | Subgroups analysis |
---|---|---|---|
SMILE Pilot | Safety of treatment | Good tolerability of zofenopril Similar CV mortality to placebo Reduced hospitalization Improved LVEF | – |
SMILE-1 | Occurrence of death or severe congestive heart failure over 6 weeks | Improved short-term 6-weeks) and long-term (1-year) outcome | Superior efficacy of zofenopril compared to placebo, also in subjects with diabetes, hypercholesterolemia, metabolic syndrome, hypertension and NSTEMI |
SMILE-2 | Occurrence of severe hypotension (SBP < 90 mmHg) at any time | Lower rate of severe hypotension with zofenopril compared to lisinopril | – |
SMILE-3 | Global ischemic burden (ischemia on 24-h ambulatory ECG, ischemia or angina during treadmill test, recurrent AMI, need for revascularization) | Zofenopril significantly reduced the frequency and severity of exertional and spontaneous cardiac ischemia It also reduced the risk of CV events | – |
SMILE-4 | Occurrence of CV mortality or hospitalization for CV causes | Efficacy of zofenopril associated with ASA superior to that of ramipril plus ASA | Superior efficacy of zofenopril compared to ramipril, also in subjects with diabetes, hypercholesterolemia, metabolic syndrome, hypertension and NSTEMI |
SMILE Overall | 1-year combined occurrence of death or hospitalization for CV causes | Occurrence of CV events was significantly reduced with zofenopril vs. placebo and vs. the other ACEIs | Efficacy superior to placebo and ramipril, but similar to lisinopril in metabolic syndrome Non-significant trend for superiority of zofenopril vs. other ACEIs in hyperuricemic patients Zofenopril superior to placebo and the other ACEIs in hypertensive subjects and in those with at least one previous CV risk factor |