Claudio Cavallini

Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis.

Objectives To compare the effects of angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, stroke, cardiovascular mortality and total mortality. Methods We conducted a meta-analysis of randomized comparative trials between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors. Inclusion criteria were publication in peer-reviewed journals indexed in Medline, randomized comparison of angiotensin II receptor blockers vs. angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers + angiotensin-converting enzyme inhibitors vs. angiotensin-converting enzyme inhibitors, report of major complications including myocardial infarction, stroke, cardiovascular mortality or all-cause mortality; average follow-up of at least 1 year in at least 200 patients. Results Six trials fulfilled the inclusion criteria, for a total of 49 924 patients. In the pooled estimate, there were no significant differences between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction (odds ratio 1.01; 95% confidence interval 0.95–1.07; P = 0.75), cardiovascular mortality (odds ratio 1.03; 95% confidence interval 0.98–1.08; P = 0.23) and total mortality (odds ratio 1.03; 95% confidence interval 0.97–1.10; P = 0.20). This was the case also when the analysis involved only the comparison between angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Overall, the risk of stroke was slightly lower with angiotensin II receptor blockers than angiotensin-converting enzyme inhibitors (odds ratio 0.92; 95% confidence interval 0.85–0.99; P = 0.037), the direct angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers comparison showing a nonsignificant trend in a similar direction. Statistical heterogeneity among trials was not significant, with a low to null inconsistency statistic, for stroke (P = 0.67), myocardial infarction (P = 0.86), cardiovascular mortality (P = 0.14) and total mortality (P = 0.12). Conclusion This overview suggests that angiotensin II receptor blockers are as effective as angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, cardiovascular mortality and total mortality. Angiotensin II receptor blockers may be slightly more protective than angiotensin-converting enzyme inhibitors on the risk of stroke.

Early Aggressive Versus Initially Conservative Treatment in Elderly Patients With Non–ST-Segment Elevation Acute Coronary Syndrome: A Randomized Controlled Trial

OBJECTIVES This study sought to determine the risk versus benefit ratio of an early aggressive (EA) approach in elderly patients with non-ST-segment elevation acute coronary syndromes (NSTEACS). BACKGROUND Elderly patients have been scarcely represented in trials comparing treatment strategies in NSTEACS. METHODS A total of 313 patients ≥ 75 years of age (mean 82 years) with NSTEACS within 48 h from qualifying symptoms were randomly allocated to an EA strategy (coronary angiography and, when indicated, revascularization within 72 h) or an initially conservative (IC) strategy (angiography and revascularization only for recurrent ischemia). The primary endpoint was the composite of death, myocardial infarction, disabling stroke, and repeat hospital stay for cardiovascular causes or severe bleeding within 1 year. RESULTS During admission, 88% of the patients in the EA group underwent angiography (55% revascularization), compared with 29% (23% revascularization) in the IC group. The primary outcome occurred in 43 patients (27.9%) in the EA group and 55 (34.6%) in the IC group (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.53 to 1.19; p = 0.26). The rates of mortality (HR: 0.87; 95% CI: 0.49 to 1.56), myocardial infarction (HR: 0.67; 95% CI: 0.33 to 1.36), and repeat hospital stay (HR: 0.81; 95% CI: 0.45 to 1.46) did not differ between groups. The primary endpoint was significantly reduced in patients with elevated troponin on admission (HR: 0.43; 95% CI: 0.23 to 0.80), but not in those with normal troponin (HR: 1.67; 95% CI: 0.75 to 3.70; p for interaction = 0.03). CONCLUSIONS The present study does not allow a definite conclusion about the benefit of an EA approach when applied systematically among elderly patients with NSTEACS. The finding of a significant interaction for the treatment effect according to troponin status at baseline should be confirmed in a larger size trial. (Italian Elderly ACS Study; NCT00510185).

Bivalirudin is superior to heparins alone with bailout GP IIb/IIIa inhibitors in patients with ST-segment elevation myocardial infarction transported emergently for primary percutaneous coronary intervention: a pre-specified analysis from the EUROMAX trial

Aims In the HORIZONS trial, in-hospital treatment with bivalirudin reduced bleeding and mortality in primary percutaneous coronary intervention (PCI) compared with heparin and routine glycoprotein IIb/IIIa inhibitors (GPI). It is unknown whether this advantage of bivalirudin is observed in comparison with heparins only with GPI used as bailout. Methods and results In the EUROMAX study, 2198 patients with ST-segment elevation myocardial infarction (STEMI) were randomized during transport for primary PCI to bivalirudin or to heparins with optional GPI. Primary and principal outcome was the composites of death or non-CABG-related major bleeding at 30 days. This pre-specified analysis compared patients receiving bivalirudin (n = 1089) with those receiving heparins with routine upstream GPI (n = 649) and those receiving heparins only with GPI use restricted to bailout (n = 460). The primary outcome death and major bleeding occurred in 5.1% with bivalirudin, 7.6% with heparin plus routine GPI (HR 0.67 and 95% CI 0.46–0.97, P = 0.034), and 9.8% with heparins plus bailout GPI (HR 0.52 and 95% CI 0.35–0.75, P = 0.006). Following adjustment by logistic regression, bivalirudin was still associated with significantly lower rates of the primary outcome (odds ratio 0.53, 95% CI 0.33–0.87) and major bleeding (odds ratio 0.44, 95% CI 0.24–0.82) compared with heparins alone with bailout GPI. Rates of stent thrombosis were higher with bivalirudin (1.6 vs. 0.6 vs. 0.4%, P = 0.09 and 0.09). Conclusion Bivalirudin, started during transport for primary PCI, reduces major bleeding compared with both patients treated with heparin only plus bailout GPI and patients treated with heparin and routine GPI, but increased stent thrombosis.

Echocardiographic left ventricular hypertrophy in hypertension: marker for future events or mediator of events?

Purpose of review To discuss the most relevant studies on the prognostic impact of echocardiographic left ventricular hypertrophy in hypertension. Recent findings There is abundant evidence from epidemiological studies that increased left ventricular mass identifies hypertensive patients at increased risk of major cardiac and cerebrovascular events. Looking at the geometric patterns of the left ventricle, concentric remodelling and concentric left ventricular hypertrophy carry the highest risk for adverse events. Patients with left ventricular hypertrophy reversal as an effect of treatment are exposed to a lesser risk of events as compared with patients with persistence of left ventricular hypertrophy. Reversal of concentric remodelling predicts a lesser risk of adverse events compared with persistence of remodelling. Experimental evidence is accumulating that several haemodynamic and nonhaemodynamic factors which are able to promote progression of atherosclerosis through plaque growth and destabilization may also induce left ventricular hypertrophy by acting on myocyte and interstitium. Increased left ventricular mass may also be a causative factor for reduced pumping performance and arrhythmias. Summary Increased left ventricular mass is a marker of cardiovascular risk because it reflects and integrates the long-term level of activity of factors inducing progression of atherosclerosis. Increased left ventricular mass may also mediate myocardial ischaemia with potential evolution towards heart failure and arrhythmias.

Blood pressure reduction and renin-angiotensin system inhibition for prevention of congestive heart failure: a meta-analysis

AIMS It is unclear whether prevention of congestive heart failure (CHF) by drugs that inhibit the renin-angiotensin system (RAS) occurs over and beyond the reduction in blood pressure (BP) achieved by these drugs. METHODS AND RESULTS We conducted a meta-analysis of trials comparing angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), or calcium-channel blockers (CCBs), with diuretics, beta-blockers, or placebo in hypertensive or high-risk subjects without CHF at entry. Both fixed- and random-effect models were used. In trials vs. placebo, the risk of CHF was reduced by 21% with ACEIs (P = 0.007), whereas the effect of ARBs and CCBs was not significant (random-effect models). Thus, CCBs did not increase the risk of CHF. In trials vs. diuretics/beta-blockers, no differences were found between ACEIs and comparators [odds ratio (OR) 1.02; 95% confidence interval (CI) 0.84-1.24], whereas CCBs were associated with an 18% higher risk of CHF (OR 1.18; 95% CI 1.00-1.39; P = 0.048). Therefore, ACEIs were not superior to diuretics/beta-blockers for the prevention of CHF. Because heterogeneity between trials was significant, we investigated potential sources of heterogeneity by meta-regression. The risk of CHF decreased by 24% (P < 0.001) for each 5 mmHg reduction in systolic BP. The risk of CHF was 19% less with ACEIs/ARBs than CCBs (P < 0.001) and 16% less in studies without multiple risk factors required for entry (P = 0.009). CONCLUSION BP reduction is beneficial for the prevention of CHF. Over and beyond BP reduction, the protective effect of ACEIs and ARBs is greater than that of CCBs.

Acute Stent Thrombosis After Primary Percutaneous Coronary Intervention : Insights From the EUROMAX Trial (European Ambulance Acute Coronary Syndrome Angiography)

OBJECTIVES This study sought to determine clinical, procedural, and treatment factors associated with acute stent thrombosis (AST) in the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial. BACKGROUND Bivalirudin started during transport for primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction significantly reduced major bleeding compared with heparin with or without glycoprotein IIb/IIIa inhibitors (GPI), but it was associated with an increase in AST. METHODS We compared patients with (n = 12) or without AST (n = 2,184) regarding baseline, clinical, and procedural characteristics and antithrombotic treatment strategies (choice of P2Y12 inhibitor, post-primary PCI bivalirudin infusion dose [0.25 mg/kg/h, or BIV-LOW] vs. [1.75 mg/kg/h, or BIV-PCI] vs. heparin ± GPI). Logistic regression was performed to identify independent correlates of AST. RESULTS The overall AST rate was 0.6% and was higher with bivalirudin than with heparin ± GPI (1.1% vs. 0.2%; p = 0.007). Median time to AST was 2.3 h (interquartile range: 1.9 to 2.8 h). Patients with AST had less hypertension (2 of 14 [14.0%] vs. 961 of 2,182 [44.0%]; p = 0.03), and more frequently received GPI (11 of 14 [78.6%] vs. 880 of 2,183 [40.3%]; p = 0.004). Multivariate analysis using Firth penalized maximum likelihood estimation found hypertension (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.07 to 0.92; p = 0.037) and BIV-LOW (OR: 5.8, 95% CI: 1.5 to 22.2; p = 0.010) predictive of AST. Choice of P2Y12 inhibitor had no impact on AST. Compared with heparin ± GPI, AST rates were higher for BIV-LOW (11 of 670 [1.6%] vs. 2 of 947 [0.2%]; p = 0.008), but not different for BIV-PCI (1 of 244 [0.4%]; p = 0.588). CONCLUSIONS In this post-hoc analysis from EUROMAX, AST occurred very early and was not mitigated by the novel P2Y12 inhibitors. Prolonging the bivalirudin infusion at the PCI dose (but not at a lower dose) appeared to mitigate the risk of AST.

The voltage of R wave in lead aVL improves risk stratification in hypertensive patients without ECG left ventricular hypertrophy.

Objectives We tested the hypothesis that the voltages of QRS on ECG improve risk stratification in hypertensive patients without left ventricular hypertrophy on ECG. Methods and results We studied 2042 initially untreated patients with hypertension (mean age 49 years, 46% women) without left ventricular hypertrophy on ECG and no history of cardiovascular disease. At entry, all patients underwent diagnostic tests, including 24-h ambulatory blood pressure monitoring and echocardiography. Among the different ECG voltages, the R wave in lead aVL showed the closest association with left ventricle (LV) mass (r = 0.31; P < 0.001), followed by the R wave in D1 (r = 0.25) and the S wave in V3 (r = 0.22). Patients were followed up for a mean of 7.7 years (range 1–22 years), and treatment was tailored individually. During follow-up, there were 188 major cardiovascular events. The relationship between LV voltage and outcome was assessed using a Cox model with adjustment for age, sex, diabetes, smoking, total cholesterol, serum creatinine, LV mass on echocardiography and average 24-h ambulatory blood pressure. A 0.1 mV higher R wave voltage in lead aVL was associated with a 9% higher risk of cardiovascular disease (95% confidence interval = 0.04–0.15%; P < 0.001). Other ECG voltages and minor repolarization changes were not related to clinical outcome. Conclusion Our results show for the first time that the voltage of the R wave in lead aVL improves cardiovascular risk stratification in hypertensive patients without left ventricular hypertrophy on ECG. Its prognostic value is independent of LV mass on echocardiography and 24-h ambulatory blood pressure.

Ambulatory Blood Pressure for Cardiovascular Risk Stratification

Ambulatory blood pressure (ABP) monitoring is increasingly recognized as a valuable tool to refine prediction of cardiovascular risk related to blood pressure (BP).1 After the first landmark study published by Perloff and colleagues 24 years ago,2 several longitudinal event-based studies provided unequivocal evidence of an independent association between ABP and risk of cardiovascular disease. Although experimental procedures and statistical analyses varied from study to study, ABP generally improved cardiovascular risk stratification over and beyond traditional risk factors, including clinic BP.3 The Table, obtained through an electronic search of literature using the terms “ambulatory blood pressure” and “prognosis,” shows a list of longitudinal event-based studies performed by independent groups. It is worth noting that the list of available studies is longer because each group generally published other analyses of their database. Only the first-appearing or main contribution from each group has been included in the Table. View this table: Longitudinal Event-Based Studies From Independent Groups That Addressed the Prognostic Value of ABP Article p 2145 Three aspects of available investigations deserve special mention. First, the prognostic value of ABP has been examined not only in subjects with clinical diagnosis of hypertension but also in the general population and in a variety of settings, including diabetes mellitus, renal failure, and cerebrovascular disease. Second, subjects could be untreated or treated at the time of ABP monitoring. This point may raise concerns, because drug treatment could exert unpredictable effects on 24-hour ABP profile and, consequently, interpretation and applicability of results. Third, although a continuous relation emerged in most studies between ABP and cardiovascular risk, several investigators tried to define clinical categories based on arbitrary thresholds of ABP. Although such categories are potentially useful to make diagnostic and therapeutic decisions in clinical practice, their prognostic role requires confirmation from large and independent cohort …

Contemporary antithrombotic strategies in patients with acute coronary syndrome admitted to cardiac care units in Italy: The EYESHOT Study

Background: Several new antithrombotic therapies have emerged for the treatment of acute coronary syndrome (ACS). We sought to assess contemporary patterns of antithrombotic therapies use in patients with ACS. Methods and results: EYESHOT (EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units) was a nationwide, prospective registry aimed to evaluate antithrombotic strategies employed in patients admitted to intensive cardiac care units (CCUs) for an ACS in Italy. Over a three-week period, 203 CCUs enrolled 2585 consecutive patients: 41.2% with ST-elevation myocardial infarction (STEMI) and 58.8% with non-ST elevation ACS (NSTE-ACS). During hospitalisation, low-molecular-weight heparins, aspirin, and clopidogrel were the most commonly used antithrombotic therapies. Among patients treated with percutaneous coronary intervention (PCI, n=1755), any crossover of heparin therapy occurred in 30.8% of cases, while switching from one P2Y12 inhibitor to another occurred in 3.6% of cases in the CathLab and in 14.2% before discharge. Of the 790 patients who did not receive revascularisation, switching of a P2Y12 inhibitor occurred in 5.7% of cases. At discharge, a new P2Y12 inhibitor (ticagrelor or prasugrel) in association with aspirin was prescribed in 59.5% of STEMI and 33.9% of NSTE-ACS patients: the most powerful predictor for prescription was PCI (odds ratio (OR) 6.18; 95% confidence interval (CI) 4.76–8.01; p<0.0001), whereas age ≥75 years was strongly associated with clopidogrel use (OR 0.28; 95% CI 0.22–0.36; p<0.0001). Conclusions: The EYESHOT registry shows the current pattern of antithrombotic treatments for ACS patients admitted to Italian CCUs and provides insights which may help to improve the clinical care of such patients.

The Prognostic Value of Creatine Kinase Elevations Extends Across the Whole Spectrum of Acute Coronary Syndromes

OBJECTIVES The study investigated the relationship among creatine kinase (CK) elevations, clinical characteristics and cardiac events across the whole spectrum of acute coronary syndromes (ACS). BACKGROUND Elevated serum levels of cardiac enzymes have been shown to be a major prognostic determinant in acute myocardial ischemia. Yet prior to this report, the relation between cardiac enzyme levels and other prognostic determinants across the entire spectrum of ACS has not been explored by a large clinical study. METHODS We evaluated the relation between the maximum CK ratio (CK level/upper limit of normal) in the early hours following admission and cardiac events at six months in 11,725 patients enrolled in a large trial of ACS. RESULTS Patients with higher risk characteristics, such as older age, female gender, hypertension, diabetes, prior coronary events or heart failure, more frequently presented without ST-segment elevation on the electrocardiogram and tended to develop lesser enzyme elevations. After adjusting for significant baseline predictors of cardiac events, a continuous correlation was observed between the CK ratio and death (chi-square 63.04, p < 0.0001) and (re)infarction or death (chi-square 55.48, p < 0.0001). This correlation was similar for patients with and without ST-segment elevation. The adjusted incidence of cardiac events at follow-up began to rise even for CK levels within the normal range, the steepest part of the curve residing between one and three times the upper limit of normal. In patients with a CK ratio of >1 to 2 compared with those within the normal range, the adjusted odds ratio for death was 1.26 (95% confidence interval [CI] 0.98 to 1.63), and 1.59 (95% CI 1.38 to 1.90) for (re)infarction and death. For all CK levels, the event rate was higher among patients without ST-segment elevation. CONCLUSIONS Although high-risk patients with ACS often develop lesser CK elevations, this study demonstrated that even minor enzyme elevations appear to have important and independent prognostic implications.