Effects of the concomitant administration of xanthine oxidase inhibitors with zofenopril or other ACE-inhibitors in post-myocardial infarction patients: a meta-analysis of individual data of four randomized, double-blind, prospective studies.

BACKGROUND: Oxidative stress is increased in hyperuricemic patients with acute myocardial infarction (AMI). Use of sulfhydryl ACE-inhibitors (ACEIs), such as zofenopril or captopril, plus xanthine oxidase inhibitors (XOIs), may potentially result in enhanced antioxidant effects and improved survival. OBJECTIVE: We verified the benefit of such combination in a randomly stratified sample of 525 of the 3630 post-AMI patients of the four randomized prospective SMILE (Survival of Myocardial Infarction Long-term Evaluation) studies. METHODS: One hundred sixty-five (31.4%) patients were treated with XOIs (79 under zofenopril, 86 placebo, lisinopril or ramipril), whereas 360 were not (192 zofenopril, 168 placebo or other ACEIs). In these four groups, we separately estimated the 1-year combined risk of major cardiovascular events (MACE, death or hospitalization for cardiovascular causes). RESULTS: MACE occurred in 10.1% of patients receiving zofenopril + XOIs, in 18.6% receiving placebo or other ACEIs + XOIs, in 13.5% receiving zofenopril without XOIs and in 22.0% receiving placebo or other ACEIs, but no XOIs (p = 0.034 across groups). Rate of survival free from MACE was significantly larger under treatment with zofenopril + XOIs than with other ACEIs with no XOIs [hazard ratio: 2.29 (1.06-4.91), p = 0.034]. A non-significant trend for superiority of zofenopril + XOIs combination was observed vs. zofenopril alone [1.19 (0.54-2.64), p = 0.669] or vs. placebo or other ACEIs + XOIs [1.82 (0.78-4.26), p = 0.169]. CONCLUSIONS: Our retrospective analysis suggests an improved survival free from MACE in post-AMI patients treated with a combination of an urate lowering drug with antioxidant activity and an ACEI, with best effects observed with zofenopril.

Efficacy of Zofenopril Compared With Placebo and Other Angiotensin-converting Enzyme Inhibitors in Patients With Acute Myocardial Infarction and Previous Cardiovascular Risk Factors: A Pooled Individual Data Analysis of 4 Randomized, Double-blind, Controlled, Prospective Studies.

In the Survival of Myocardial Infarction Long-term Evaluation (SMILE) 1, 3, and 4 studies, early administration of zofenopril in acute myocardial infarction showed to be prognostically beneficial versus placebo or ramipril. The SMILE-2 showed that both zofenopril and lisinopril are safe and showed no significant differences in the incidence of major cardiovascular (CV) complications. In this pooled analysis of individual data of the SMILE studies, we evaluated whether the superior efficacy of zofenopril is maintained also in patients with ≥1 CV risk factor (CV+, n = 2962) as compared to CV- (n = 668). The primary study end point was set to 1-year combined occurrence of death or hospitalization for CV causes. The risk of CV events was significantly reduced with zofenopril versus placebo either in the CV+ (-37%; hazard ratio: 0.63; 95% confidence interval: 0.51-0.78; P = 0.0001) or in the CV- group (-55%; hazard ratio: 0.45; 0.26-0.78; P = 0.004). Also, the other angiotensin-converting enzyme inhibitors reduced the risk of major CV outcomes, though the reduction was not statistically significant versus placebo (CV+: 0.78; 0.58-1.05; P = 0.107; CV-: 0.71; 0.36-1.41; P = 0.334). The benefit was larger in patients treated with zofenopril than other angiotensin-converting enzyme inhibitors, with a statistically significant difference for CV+ (0.79; 0.63-0.99; P = 0.039) versus CV- (0.62; 0.37-1.06; P = 0.081). In conclusion, zofenopril administered to patients after acute myocardial infarction has a positive impact on prognosis, regardless of the patient's CV risk profile.

Cardioprotective role of zofenopril in hypertensive patients with acute myocardial infarction: a pooled individual data analysis of the SMILE studies.

PURPOSE: The four SMILE studies demonstrated that early administration of zofenopril following acute myocardial infarction is prognostically beneficial compared to placebo or other angiotensin-converting enzyme (ACE) inhibitors. In the present retrospective pooled analysis of individual SMILE studies, we evaluated the efficacy of zofenopril on cardiovascular (CV) outcomes in 1880 hypertensive and 1662 normotensive patients. MATERIALS AND METHODS: Four hundred and forty-nine hypertensives and 486 normotensives were treated with placebo, 980 and 786 with zofenopril 30-60 mg daily, 252 and 259 with lisinopril 5-10 mg daily, 199 and 131 with ramipril 10 mg daily, for 6 to 48 weeks. RESULTS: The 1-year risk of death or hospitalization for CV causes was significantly reduced with zofenopril and lisinopril vs. placebo in both hypertensive (HR: 0.65; 95%CI: 0.48-0.86; p = .003 and .60, .36-.99; p = .049, respectively) and normotensive patients (0.56, 0.42-0.75; p = .0001 and .51, .28-.90; p = .020), whereas this was not the case for ramipril (hypertensives: 1.02, 0.69-1.52; p = .918; normotensives: 0.91, 0.59-1.41; p = .670). Zofenopril significantly reduced the risk of CV outcomes vs. the other two ACE-inhibitors pooled together in hypertensive (0.76; 0.58-0.99; p = .045), but not in normotensive patients (0.77; 0.55-1.10; p = .150). CONCLUSIONS: In cardiac patients of the SMILE studies with arterial hypertension treatment with the ACE-inhibitor zofenopril was beneficial in reducing the 1-year risk of CV events as compared to placebo and ramipril. An efficacy similar to that of zofenopril was observed with lisinopril.

Enhancing stroke risk prediction in patients with transient ischemic attack: insights from a prospective cohort study implementing fast-track care.

Background and aims: Fast-track care have been proved to reduce the short-term risk of stroke after transient ischemic attack (TIA). We aimed to investigate stroke risk and to characterize short- and long-term stroke predictors in a large cohort of TIA patients undergoing fast-track management. Methods: Prospective study, enrolling consecutive TIA patients admitted to a Northern Italy emergency department from August 2010 to December 2017. All patients underwent fast-track care within 24 h of admission. The primary outcome was defined as the first stroke recurrence at 90 days, 12 and 60 months after TIA. Stroke incidence with 95% confidence interval (CI) at each timepoint was calculated using Poisson regression. Predictors of stroke recurrence were evaluated with Cox regression analysis. The number needed to treat (NNT) of fast-track care in preventing 90-day stroke recurrence in respect to the estimates based on baseline ABCD2 score was also calculated. Results: We enrolled 1,035 patients (54.2% males). Stroke incidence was low throughout the follow-up with rates of 2.2% [95% CI 1.4-3.3%] at 90 days, 2.9% [95% CI 1.9-4.2%] at 12 months and 7.1% [95% CI 5.4-9.0%] at 60 months. Multiple TIA, speech disturbances and presence of ischemic lesion at neuroimaging predicted stroke recurrence at each timepoint. Male sex and increasing age predicted 90-day and 60-month stroke risk, respectively. Hypertension was associated with higher 12-month and 60-month stroke risk. No specific TIA etiology predicted higher stroke risk throughout the follow-up. The NNT for fast-track care in preventing 90-day stroke was 14.5 [95% CI 11.3-20.4] in the overall cohort and 6.8 [95% CI 4.6-13.5] in patients with baseline ABCD2 of 6 to 7. Conclusion: Our findings support the effectiveness of fast-track care in preventing both short- and long-term stroke recurrence after TIA. Particular effort should be made to identify and monitor patients with baseline predictors of higher stroke risk, which may vary according to follow-up duration.

Laboratory and Instrumental Risk Factors Associated with a Sudden Cardiac Death Prone ECG Pattern in the General Population: Data from the Brisighella Heart Study.

Sudden cardiac death (SCD) remains a daunting problem and a major public health issue. We applied the validated Electrocardiogram (ECG) score to the Brisighella Heart Study (BHS) cohort, in order to verify if there were also other recognized laboratory and instrumental risk factors for cardiovascular disease associated with a sudden death risk-prone pattern. We examined the ECG traces of 1377 participants of the 2016 BHS survey and identified 33 subjects at high risk for SCD (while 1344 subjects had no cumulative ECG abnormalities). Serum uric acid (SUA) and carotid-femoral pulse wave velocity (cfPWV) values were significantly higher in the high-risk cohort (p < 0.05) and were both independently associated with the presence of ECG abnormalities [Odd ratio (OR) = 2.14, p < 0.05-OR = 1.23, p < 0.05, respectively]. A similar independent correlation was found with long-term non-steroid anti-inflammatory drugs (NSAIDs) use, more widespread among high-risk subjects (OR = 1.19, p < 0.05). Conversely, the analysis did not show any significant association with impaired renal function (p = 0.09). This study showed that long-term NSAID use and high SUA and cfPWV values are independent risk factors for ECG abnormalities predictive of SCD. These findings herald the need for further prospective research to identify the optimal combination of SCD risk markers in order to prevent fatal events.

Long-term consequences of previous preeclampsia and complicated pregnancy: analysis of echocardiographic aspects.

AIM: To evaluated echocardiographic aspects in women with history of preeclampsia or preeclampsia-related complications in their previous pregnancies. MATERIALS AND METHODS: Consecutive women receiving echocardiography during daily clinical echolab activity were studied using complete echocardiographic examination data and anamnestic data collection of hypertension, diabetes, dyslipidemia, and rheumatic diseases. Studied women should have at least one pregnancy in more than the 10 past years, and were subdivided into two groups according to the history of complicated or physiological pregnancy. Complicated pregnancies were defined by preeclampsia or preeclampsia-related complication, such as preterm delivery or small-for-gestational age newborn. Echocardiographic parameters and prevalence of hypertension, diabetes, dyslipidemia, and rheumatic disease were compared between the two groups of studied women. RESULTS: From March 2016 to May 2020, 545 women were studied, of whom 218 had a history of complicated pregnancy (mean age 60.81 ±â€Š11.109 years vs. 62.78 ±â€Š9.758 years of not complicated pregnancy; P = 0.03). Compared with physiological pregnancy women, complicated pregnancy ones were shorter (159.97 ±â€Š6.608 vs. 161.42 ±â€Š6.427 cm; P = 0.012) with lower body surface area (1.678 ±â€Š0.1937 vs. 1.715 ±â€Š0.1662 m2; P = 0.02), had higher prevalence of diabetes (6.9 vs. 3.1%; P = 0.04; odds ratio = 2.34; CI 1.0323--5.3148) and rheumatic diseases (33 vs. 22.3%; P = 0.006; odds ratio = 1.72; CI 1.1688--2.5191), and showed a slight, not significant higher prevalence of hypertension. As for echocardiographic parameters, they showed significantly higher values of end-diastolic left ventricular posterior wall (LPWd) (P = 0.034), a trend toward a more concentric geometry, and a worse longitudinal systolic left and right ventricle performance, represented by lower tissue Doppler systolic waves (septal: 7.41 ±â€Š1.255 vs. 7.69 ±â€Š1.376 cm/s; P = 0.018; and tricuspidalic: 12.64 ±â€Š2.377 vs. 13.32 ±â€Š2.548 cm/s; P = 0.003). CONCLUSION: Patients with previous preeclampsia present an increased risk of hypertension, diabetes, and rheumatic diseases, suggesting that these women could share a specific predisposition to a high-risk profile. Furthermore, they show a higher prevalence of classically considered echocardiographic hypertensive-derived cardiac damage, suggesting structural and functional left ventricular modifications as subclinical aspects of long-term worse cardiovascular prognosis for these women.

Left atrial volume indexed for height2 is a new sensitive marker for subclinical cardiac organ damage in female hypertensive patients.

Left atrial enlargement (LAe) is a subclinical marker of hypertensive-mediated organ damage, which is important to identify in cardiovascular risk stratification. Recently, LA indexing for height was suggested as a more accurate marker of defining LAe. Our aim was to test the difference in LAe prevalence using body surface area (BSA) and height2 definitions in an essential hypertensive population. A total of 441 essential hypertensive patients underwent complete clinical and echocardiographic evaluation. Left atrial volume (LAV), left ventricular morphology, and systolic-diastolic function were evaluated. LAe was twice as prevalent when defined using height2 (LAeh2) indexation rather than BSA (LAeBSA) (51% vs. 23%, p < 0.001). LAeh2, but not LAeBSA, was more prevalent in females (p < 0.001). Males and females also differed in left ventricular hypertrophy (p = 0.046) and left ventricular diastolic dysfunction (LVDD) indexes (septal Em/Etdi: p = 0.009; lateral Em/Etdi: p = 0.003; mean Em/Etdi: p < 0.002). All patients presenting LAeBSA also met the criteria for LAeh2. According to the presence/absence of LAe, we created three groups (Norm = BSA-/h2-; DilH = BSA-/h2+; DilHB = BSA+/h2+). The female sex prevalence in the DilH group was higher than that in the other two groups (Norm: p < 0.001; DilHB: p = 0.036). LVH and mean and septal Em/Etdi increased from the Norm to the DilH group and from the DilH to the DilHB group (p < 0.05 for all comparisons). These results show that LAeh2 identified twice as many patients as comparing LAe to LAeBSA, but that both LAeh2 and LAeBSA definitions were associated with LVH and LVDD. In female patients, the LAeh2 definition and its sex-specific threshold seem to be more sensitive than LAeBSA in identifying chamber enlargement.

Effects of sacubitril valsartan on clinical and echocardiographic parameters of outpatients with heart failure and reduced ejection fraction.

AIM: Sacubitril valsartan (SV) has revolutionized disease history in patients with heart failure and reduced ejection fraction (HFrEF). Our study assessed SV impact on clinical and echocardiographic parameters in HFrEF outpatients previously treated with optimized therapy. METHODS: Forty-nine HFrEF outpatients were retrospectively included in the study. We collected data from transthoracic echocardiography and clinical assessment at baseline and after 3 ± 1 and 12 ± 1 months of treatment with SV. Results were also stratified by sex to analyse possible sex-based differences in reverse remodelling response to SV. RESULTS: After 3 months of treatment we observed a significative improvement of both systolic and diastolic function with a reduction of left ventricular mass and relative wall thickness (RWT). At 12 months we observed a further improvement of all previous parameters, plus systolic pulmonary artery pressure (PAP) and left atrial (LA) diameter. In women, most of the echocardiographic parameters improved after SV initiation, but did not reach the statistical significance, except for left ventricular ejection fraction (LVEF), PAP and LA diameter. As for clinical parameters, SV improved New York Heart Association (NYHA) Class, systolic blood pressure and loop diuretic dosage with a mild but significative increase in serum creatinine and potassium. CONCLUSION: Our study showed significative reverse remodelling properties of SV with an improvement of LV volumes, mass and systo-diastolic function. NYHA Class, systolic blood pressure and loop diuretic dosage also improved with only mild increase in serum creatinine and potassium. Women showed a lesser extent of reverse remodelling compared with men.

Efficacy of zofenopril in combination with amlodipine in patients with acute myocardial infarction: a pooled individual patient data analysis of four randomized, double-blind, controlled, prospective studies.

OBJECTIVE: In the four SMILE (Survival of Myocardial Infarction Long-Term Evaluation) studies, early administration of zofenopril in acute myocardial infarction (AMI) showed beneficial effects as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs). This study investigated whether the concomitant administration of the dihydropyridine calcium channel-blocker amlodipine may improve zofenopril efficacy to prevent cardiovascular events in post-AMI patients. METHODS: This was a post-hoc analysis of pooled individual patient data from the four large randomized SMILE studies. The primary endpoint was the 1-year combined occurrence of death or hospitalization for cardiovascular causes. RESULTS: In total, 3488 patients were considered, 303 (8.7%) treated with concomitant amlodipine. Baseline systolic blood pressure and prevalence of metabolic syndrome were higher in amlodipine treated patients. The 1-year occurrence of major cardiovascular outcomes was significantly reduced in patients receiving concomitant treatment with amlodipine (hazard ratio, HR = 0.66; and 95% confidence interval, CI = 0.44-0.98; p = .039). After accounting for treatment with amlodipine, the risk of cardiovascular events was significantly reduced with zofenopril compared to placebo (HR = 0.78; 95% CI = 0.63-0.97; p = .026]. Among ACEI-treated patients, the zofenopril plus amlodipine combination reduced the risk of cardiovascular events by 38%, compared to the combination of other ACEIs plus amlodipine [HR = 0.76; 95% CI = 0.61-0.94); p = .013). The prognostic benefit of concomitant treatment with zofenopril plus amlodipine was independent from blood pressure lowering. CONCLUSIONS: Zofenopril had a positive impact on prognosis in post-AMI patients, compared to other ACEIs. Concomitant administration of amlodipine may help to reduce the risk of cardiovascular events at 1 year.

Efficacy of zofenopril in combination with thiazide diuretics in patients with acute myocardial infarction: a pooled individual data analysis of four randomized, double-blind, controlled, prospective studies.

BACKGROUND: In the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) studies, early administration of zofenopril after acute myocardial infarction (AMI) was prognostically beneficial as compared to placebo and other angiotensin-converting enzyme inhibitors (ACEIs), such as lisinopril and ramipril. Here, we investigated whether zofenopril efficacy could be affected by a concomitant use of thiazide diuretics (TDs). METHODS: This was a post hoc analysis of pooled individual patient data from the SMILE studies. Patients treated with other diuretics than TDs were excluded. The primary study endpoint was the 1-year combined occurrence of death or hospitalization for CV causes, with or without TD. RESULTS: Among 2,995 patients, 263 (8.8%) were treated with a combination including a TD (TD+), whereas 2,732 (91.2%) were not treated with any diuretic (TD-). Proportions of subjects who were treated with TD were equally distributed (p=0.774) within the placebo, zofenopril, and other ACEIs groups. The 1-year risk of major cardiovascular events was similar in TD+ (18.3%) and TD- (16.8%) patients (hazard ratio [HR] 1.04; 95% CI 0.74-1.45; p=0.838). After stratifying per concomitant treatment and TD, the 1-year risk of CV events was significantly lower with zofenopril than with placebo (HR 0.70; 95% CI 0.55-0.88; p=0.002) and other ACEIs (HR 0.58; 95% CI 0.46-0.74; p=0.0001). Treatment with ACEIs and TD as concomitant therapy was associated with a larger blood pressure (BP) reduction (p=0.0001 for systolic BP and p=0.045 for diastolic BP). CONCLUSION: In post AMI patients, zofenopril maintained its positive impact on prognosis compared to placebo or other ACEIs, regardless concomitant TD administration. In this setting, TD shows advantages in managing the most difficult hypertensive patients.

Echocardiographic characteristics of hypertensive patients affected by transient ischemic attack: a cross-sectional study.

Atrial septal aneurysm (ASA), common finding in normal echocardiographies, has been described in association with transient ischemic attacks (TIAs)/strokes, as well as hypertensive end-organ damage such as left ventricular (LV) hypertrophy. Aim of this study was to assess if a cluster of echocardiographic aspects could characterize TIA hypertensive patients. A cross-sectional study on patients with history of TIA, referring to a Hypertension Center echolab, has been performed. A total of 5223 patients received transthoracic echocardiography. TIA patients were 292 (5.6%). A total of 102 age/sex-matched patients without TIA have been collected as controls. The main characteristic of TIA patients resulted ASA/bulging (B) (TIA 61%, controls 6%, P = .0001). Other aspect was LV concentric remodeling (TIA 32.3%, controls 20.8%, P = .029) and mitral flow aspects of diastolic dysfunction. After adjustment for age and hypertension, ASA/B (odds ratio [OR] = 62.4, 95% confidence interval [CI]: 13.6-73.9, P < .001), followed by LV concentric hypertrophy (OR = 2.1, 95% CI: 1.1-4.3, P = .043), was associated with a positive TIA history. A binary logistic regression performed in ASA/B patients, identified relative wall thickness as the strongest TIA-associated aspect (OR = 53.4, 95% CI: 11.9-74.18, P = .001). ASA/B, common finds in general population, could carry a significant incremental possibility of association with TIA when concentric geometry, frequent hypertensive aspect, is present as well.

Effects of early angiotensin-converting enzyme inhibition in patients with non-ST-elevation acute anterior myocardial infarction.

BACKGROUND: No data are available on the clinical efficacy of the early administration (<24 hours from onset of chest pain) of angiotensin-converting enzyme inhibitors in non-thrombolysed patients with non-ST-elevation myocardial infarction (NSTEMI). We have addressed this issue in a subgroup of NSTEMI patients enrolled in the SMILE trial. METHODS: Of the overall population of 1556 patients, 526 (33.8%) had an anterior wall NSTEMI, defined as an ST elevation <1 mm or an ST depression in at least two contiguous precordial leads with or without new abnormal Q waves. No patient of the SMILE Study received thrombolytic therapy or was reperfused. Patients were randomized, double-blind, to zofenopril (n = 253) or placebo (n = 273) for 6 weeks. The primary end point was the effect of treatment on the 6-week combined occurrence of death and severe congestive heart failure (CHF). Secondary end points included the evaluation of the 6-week rate of severe CHF as well as the 1-year mortality rate. RESULTS: After 6 weeks of treatment, zofenopril significantly reduced both the incidence of the primary end point (risk reduction 65%, 95% CI 20-80, 2P = .003) and the 6-week incidence of severe CHF (84%, 95% CI 33-97, 2P = .006) in NSTEMI patients. One-year mortality was also significantly reduced by zofenopril treatment (43%, 95% CI 14-57, 2P = .036). CONCLUSIONS: Results of this post hoc analysis of the SMILE Study strongly suggest the benefit of the early administration of zofenopril even in patients with an anterior wall NSTEMI.

Effects of the early ACE inhibition in diabetic nonthrombolyzed patients with anterior acute myocardial infarction.

OBJECTIVE: The aim of the present study was to evaluate the clinical efficacy of the ACE inhibitor zofenopril in a cohort of diabetic patients with nonthrombolyzed anterior acute myocardial infarction who were enrolled in the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) trial. RESEARCH DESIGN AND METHODS: Among the overall population of 1,512 patients, 303 (20.0%) had diabetes. The primary end point of this study was the effect of treatment on the 6-week combined occurrence of death and severe congestive heart failure (CHF). Secondary end points included the evaluation of the 6-week rate of major cardiovascular events as well as the 1-year survival rate. RESULTS: After 6 weeks of double-blind treatment, zofenopril significantly reduced both the incidence of the primary end point (8.6 vs. 18.3%; P = 0.019) and the 6-week incidence of severe CHF (0 vs. 7.3%; P = 0.001) in diabetic patients, and the effect was greater than that observed in nondiabetic patients. Conversely, 1-year mortality was significantly reduced among nondiabetic patients (9.1 vs. 13.8%; P = 0.010), whereas in the diabetic population, the decrease did not reach statistical significance (13.7 vs. 16.5%; P = 0.52). CONCLUSIONS: The present data suggest that the clinical outcome of patients with diabetes and myocardial infarction can be significantly improved by early treatment with zofenopril. The lesser effect on 1-year mortality seems to suggest that long-term treatment is probably needed to maintain the benefits of the early ACE inhibition in patients with diabetes.

Cardioprotective role of zofenopril in patients with acute myocardial infarction: a pooled individual data analysis of four randomised, double-blind, controlled, prospective studies.

BACKGROUND: Early administration of zofenopril following acute myocardial infarction (AMI) proved to be prognostically beneficial in the four individual randomised, double-blind, parallel-group, prospective SMILE (Survival of Myocardial Infarction Long-term Evaluation) studies. In the present analysis, we evaluated the cumulative efficacy of zofenopril by pooling individual data from the four SMILE studies. METHODS: 3630 patients with AMI were enrolled and treated for 6-48 weeks with zofenopril 30-60 mg/day (n=1808), placebo (n=951), lisinopril 5-10 mg/day (n=520) or ramipril 10 mg/day (n=351). The primary study end point of this pooled analysis was set to 1 year combined occurrence of death or hospitalisation for cardiovascular (CV) causes. RESULTS: Occurrence of major CV outcomes was significantly reduced with zofenopril versus placebo (-40%; HR=0.60, 95% CI 0.49 to 0.74; p=0.0001) and versus the other ACE inhibitors (-23%; HR=0.77, 0.63 to 0.95; p=0.015). The risk reduction observed under treatment with the other ACE inhibitors was nearly statistically significant (-22%; HR=0.78, 0.60 to 1.02; p=0.072). The benefit of zofenopril versus placebo was already evident after the first 6 weeks of treatment (-28%; HR=0.72, 0.54 to 0.97; p=0.029), while this was not the case for the other ACE inhibitors (-19%; HR=0.81, 0.57 to 1.17; p=0.262). In this early phase of treatment, zofenopril showed a non-significant trend towards a larger reduction in CV events versus the other ACE inhibitors (-11%; HR=0.89, 0.69 to 1.15; p=0.372). CONCLUSIONS: The pooled data analysis from the SMILE Programme confirms the favourable effects of zofenopril treatment in patients with post-AMI and its long-term benefit in terms of prevention of CV morbidity and mortality.

Randomised comparison of zofenopril and ramipril plus acetylsalicylic acid in postmyocardial infarction patients with left ventricular systolic dysfunction: a post hoc analysis of the SMILE-4 Study in patients according to levels of left ventricular ejection fraction at entry.

OBJECTIVE: Conflicting evidence exists on the benefits of treating patients with coronary artery disease and preserved left ventricular ejection fraction (LVEF) with an ACE inhibitor. This retrospective analysis of the SMILE-4 Study sought to compare the efficacy of zofenopril 60 mg plus acetylsalicylic acid (ASA) versus ramipril 10 mg plus ASA 100 mg in patients with acute myocardial infarction (AMI) and heart failure, according to an impaired or preserved LVEF. METHODS: The primary study end point was 1-year combined occurrence of death or hospitalisation for cardiovascular causes. A preserved LVEF was defined by a baseline LVEF >40% and an impaired one by an LVEF ≤40%. RESULTS: 448 patients (63%) had preserved and 262 (37%) had impaired LVEF. The primary end point occurred in 125 patients with preserved (28%) and 106 patients with impaired LVEF (41%, p=0.001). In the first group, the rate of major cardiovascular events was significantly lower under zofenopril than under ramipril (23% vs 33%; OR and 95% CI 0.60, 0.39 to 0.91; p=0.016). This was also the case for patients with impaired LVEF, though between-group difference was not statistically significant (38% zofenopril vs 44% ramipril; OR 0.77, 0.47 to 1.26; p=0.297). LVEF values significantly (p<0.0001) increased during the follow-up in both subsets with no between-treatment differences. However, improvement rates in LVEF (increase ≥5%) were higher in patients with impaired LVEF (72% vs 61%, p=0.006). CONCLUSIONS: In the SMILE-4 Study, the cardiovascular outcome of patients with post-AMI with preserved LVEF was more favourable in the zofenopril than in the ramipril treatment group. TRIAL REGISTRATION NUMBER: EudraCT Number: 2004-001150-88 (http://www.clinicaltrialsregister.eu); Italian Ministry of Health Code: GUIDOTT_III_2004_001 (https://oss-sper-clin.agenziafarmaco.it).

Serum uric acid and other short-term predictors of electrocardiographic alterations in the Brisighella Heart Study cohort.

INTRODUCTION: Recent studies show that serum uric acid (SUA) is a predictor of atrial fibrillation, while its association with other kinds of arrhythmias is not yet established. We aimed to evaluate the incidence of the most common electrocardiographic alterations in a relatively large sample of general population and their association with SUA. MATERIALS AND METHODS: We selected a Brisighella Heart Study cohort sample of 1557 subjects, consecutively visited in the 2004 and 2008 surveys, in a setting of primary prevention for cardiovascular disease and without a known diagnosis of arrhythmia or left ventricular hypertrophy, excluding subjects affected by gout or taking any antihyperuricemic agent or drugs able to interfere with the QT interval. A step-wise Cox regression analysis was used to determine the independent prognostic significance of age, gender, physical activity, smoking, body mass index (BMI), fasting plasma glucose, mean arterial pressure (MAP), heart rate, LDL-cholesterol, HDL-cholesterol, triglycerides, SUA and eGFR on ECG alterations during a 4-year follow-up. RESULTS: No one of the considered variables was associated with the incident diagnosis of sinus tachycardia and sinus bradycardia. SUA predicted incident tachyarrhythmias, Q waves and ECG signs of left ventricular hypertrophy; age, female sex and active smoking predicted incident tachyarrhythmias; male sex, active smoking and LDL-cholesterol predicted incident ECG signs of previous myocardial infarction; BMI and MAP predicted incident ECG-diagnosed left ventricular hypertrophy. CONCLUSION: In a cohort of general population, SUA seems to be a significant middle-term predictor of electrocardiographically diagnosed myocardial infarction, left ventricular hypertrophy and tachyarrhythmias.

Serum cholesterol levels, blood pressure response to stress and incidence of stable hypertension in young subjects with high normal blood pressure.

RATIONALE: Elevated serum cholesterol levels are common in patients with high blood pressure (BP) and could contribute to the progression of the hypertensive disease. OBJECTIVE: To determine whether serum cholesterol levels affect the BP response to mental stress (MA) and the development of stable hypertension in young subjects with high normal BP. METHODS: Seventy young (age < 45 years) high normal BP subjects with elevated (> 200 mg/dl, n = 49; HC) or normal (< or = 199 mg/dl, n = 21; NC) serum cholesterol levels, and 20 normotensive normocholesterolaemic (serum cholesterol < 199 mg/dl; C) subjects undergoing standardized mental challenge (mental arithmetic) were followed up for 15 years according to a prospective, longitudinal, cohort study design conducted in an ambulatory setting. The main outcome measure was the evaluation of the 15-year incidence of stable hypertension (diastolic BP > 95 mmHg). RESULTS: After adjustment for age, resting BP, family history of high BP and body mass index at the study entry, high normal BP subjects with HC showed an enhanced BP reactivity to stress and a higher 15-year incidence of stable hypertension compared to high normal BP and NC subjects [relative risk (RR) = 2.1; 95% confidence interval (CI) = 1.7-5.5, P < 0.001] and controls (RR = 3.1; 95% CI = 1.4-5.3, P < 0.001). In a multivariate analysis of data the presence of high cholesterol levels was an independent predictor for the development of hypertension. CONCLUSION: These data suggest that subjects with high normal BP and elevated serum cholesterol might have an exaggerated cardiovascular response to stress and have an increased risk for stable hypertension that can be detected at young age.

Efficacy and tolerability of delapril plus indapamide versus lisinopril plus hydrochlorothiazide combination treatments in mild to moderate hypertension: a multicenter, randomized clinical study.

BACKGROUND: Several studies have shown that antihypertensive monotherapy is commonly insufficient to control blood pressure (BP) in hypertensive patients and that concomitant use of ≥2 drugs is necessary in ∼50% of these patients. The combination of an angiotensin-converting enzyme (ACE) inhibitor and a diuretic, delapril plus indapamide (D + I), has been shown to be effective and tolerable, with no interaction between the 2 components. Another widely used combination of ACE inhibitor and diuretic is lisinopril plus hydrochlorothiazide (L + H). OBJECTIVES: The aims of this study were to confirm the antihypertensive efficacy and tolerability of the fixed combination of D + I in mild to moderate hypertension, and to compare its therapeutic efficacy and tolerability with that of L + H. METHODS: The antihypertensive efficacy and tolerability of a fixed combination of D + I (30-mg + 2.5-mg tablets once daily) or L + H (20-mg + 12.5-mg tablets once daily) in patients with mild to moderate hypertension were compared in a multinational, multicenter, randomized, 2-armed, parallel-group study. Eligible patients were aged 18 to 75 years and had a diastolic blood pressure (DBP) 95 to 115 mm Hg and a systolic blood pressure (SBP) ≤180 mm Hg, both measured in the sitting position. After a single-blind, placebo run-in period of 2 weeks, patients were randomized to receive 1 of the 2 treatments for a 12-week period. The primary efficacy end point was the BP normalization rate (ie, the percentage of patients with a sitting DBP ≤90 mm Hg) after 12 weeks of treatment. Secondary end points were as follows: (1) the responder rate (ie, the percentage of patients whose sitting DBP was reduced by ≥10 mm Hg from baseline or had a DBP ≤90 mm Hg after 12 weeks of treatment), (2) the percentage of patients with a DBP ≤85 mm Hg, and (3) changes in sitting SBP and DBP after 4, 8, and 12 weeks of treatment. RESULTS: A total of 159 hypertensive patients (88 women, 71 men) were randomized to receive D + I (44 women, 36 men; mean [SD] age, 53 [(11)] years) or L + H (44 women, 35 men; mean [SD] age, 55 [(10)] years). No significant between-group differences were found in any of the primary or secondary end points of the study. Both combinations induced a significant reduction in sitting DBP and SBP from baseline (P<0.001 for both groups at week 12), without significant differences between the groups. Five mild to moderate adverse drug reactions (ADRs) occurred in each treatment group. No patient dropped out of the study because of an ADR. CONCLUSION: This study showed no difference between D + I and L + H interms of antihypertensive efficacy or tolerability in patients with mild to moderate hypertension.

Zofenopril and ramipril and acetylsalicylic acid in postmyocardial infarction patients with left ventricular systolic dysfunction: a retrospective analysis in hypertensive patients of the SMILE-4 study.

BACKGROUND: Antecedent hypertension represents a risk factor for adverse outcomes in survivors of acute myocardial infarction (AMI). Prognosis of such patients might be greatly improved by drugs enhancing blood pressure control. In the present retrospective analysis of the randomized, double-blind, parallel-group, SMILE-4 study we compared the efficacy of zofenopril 60 mg and acetylsalicylic acid (ASA) 100 mg versus ramipril 10 mg and ASA in patients with AMI complicated by left ventricular dysfunction, classified according to a history of hypertension. METHODS: The primary study end-point was 1-year combined occurrence of death or hospitalization for cardiovascular causes. Hypertension was defined according to medical history and current blood pressure values at entry and could be determined in 682 of 716 patients of the intention-to-treat analysis. RESULTS: One hundred and fifty-seven patients (23%) were normotensives and 525 (77%) hypertensives. In the normotensive population the primary end-point occurred in 19 of 76 zofenopril-treated patients (25%) and in 23 of 81 ramipril-treated patients (28%) [odds ratio (95% confidence interval): 0.84 (0.41-1.71), P = 0.631]. In the hypertensive population, major cardiovascular outcomes were reported in 84 of 273 zofenopril-treated patients (31%) and in 99 of 252 ramipril-treated patients (39%), with a 31% significantly (P = 0.041) lower risk with zofenopril [0.69 (0.48-0.99)]. The superiority of zofenopril versus ramipril was particularly evident in patients with isolated systolic hypertension [n = 131, 0.48 (0.23-0.99), P = 0.045]. CONCLUSION: This retrospective analysis of the SMILE-4 study confirmed the good efficacy of zofenopril and ASA in the prevention of long-term cardiovascular outcomes also in the subgroup of patients with hypertension.