Roberto R. Giraldez

Baseline Low-Density Lipoprotein Cholesterol Is an Important Predictor of the Benefit of Intensive Lipid-Lowering Therapy: A PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) Analysis

OBJECTIVESnThis study sought to determine whether the benefit of intensive lipid-lowering therapy (LLT) is dependent on baseline low-density lipoprotein cholesterol (LDL-C).nnnBACKGROUNDnAggressive LDL-C reduction with statins improves cardiovascular outcomes in acute and chronic coronary heart disease (CHD). The importance of baseline LDL-C is unclear.nnnMETHODSnWe compared 2-year composites of death, myocardial infarction (MI), unstable angina, revascularization >30 days, and stroke (primary end point), and CHD death, MI, and revascularization >30 days (secondary end point) in 2,986 statin-naïve patients with recent acute coronary syndrome (ACS) randomized to atorvastatin 80 mg versus pravastatin 40 mg in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) study stratified by quartiles of baseline LDL-C. Multivariable models assessed whether the treatment benefit was dependent on baseline LDL-C.nnnRESULTSnA significant reduction in the hazards of the primary (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.47 to 0.85, p = 0.002) and secondary (HR: 0.57, 95% CI: 0.42 to 0.79, p = 0.001) end points occurred in patients within the highest quartile (>132 mg/dl) of baseline LDL-C treated with atorvastatin 80 mg. The benefit of intensive therapy progressively declined as baseline LDL-C decreased. The lowest quartile (LDL-C < or =92 mg/dl) experienced similar rates of the primary (HR: 0.93, 95% CI: 0.69 to 1.25, p = 0.63) and secondary (HR: 0.98, 95% CI: 0.71 to 1.35, p = 0.89) end points. Adjusted interaction tests between treatment and highest versus lowest baseline LDL-C quartile were significant for the primary and secondary end points (p = 0.03 and p = 0.007, respectively). Analyzing baseline LDL-C as a continuous variable, atorvastatin 80 mg was associated with improved outcomes provided the baseline LDL-C was >66 mg/dl.nnnCONCLUSIONSnA progressive reduction in the benefit of intensive LLT with atorvastatin 80 mg over pravastatin 40 mg occurred in statin-naïve ACS patients as baseline LDL-C declined. (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 [PROVE IT-TIMI 22]; NCT00382460).

The Anti-anginal Drug Trimetazidine Reduces Neutrophil-mediated Cardiac Reperfusion Injury

Trimetazidine has no hemodynamic/antithrombotic actions. Hence, its anti-ischemic properties have been mostly attributed to its metabolic effects. However, this issue is not completely elucidated. We investigated whether inhibition of neutrophil activation may also contribute to its cardioprotective action. We first showed that trimetazidine inhibits neutrophil activation in vitro. We subsequently tested whether trimetazidine protects postischemic hearts from neutrophil-mediated injury. Four groups of rat hearts underwent 20 minutes of global ischemia: (1) controls, reperfused with neutrophil-enriched buffer for 5 minutes, followed by 40 minutes standard perfusate; (2) hearts from rats pretreated with trimetazidine for 1 week; (3) hearts in which 10−6 M trimetazidine was added to the perfusate, starting 5 minutes before ischemia and for the initial 15 minutes of reflow; (4) hearts from pretreated rats that also received trimetazidine in the perfusate. Postischemic impairment of contractile function was significantly attenuated by trimetazidine infusion (recovery of developed pressure: 68 ± 7% versus 42 ± 9% of baseline in controls; P < 0.05). Pretreatment alone was not effective, nor did it further improve the beneficial effects of infusion. Cardiac oxygen radical production at reflow (by electron paramagnetic resonance spectroscopy) was also reduced by trimetazidine, independently of direct scavenger effects. Thus, trimetazidine can protect postischemic hearts from neutrophil-mediated injury.

Relations between bleeding and outcomes in patients with ST-elevation myocardial infarction in the ExTRACT-TIMI 25 trial

AIMSnTo evaluate the association of bleeding with mortality in ST-elevation myocardial infarction (STEMI).nnnMETHODS AND RESULTSnWe studied 20 323 patients with STEMI receiving fibrinolytic therapy and an antithrombin in ExTRACT-TIMI 25. Relationships between in-hospital bleeding, patient characteristics, treatments, and in-hospital cardiovascular complications with mortality were evaluated using Cox models. Likelihood ratios estimated each variables model contribution. High 30-day mortality after major bleeding (n = 309, 37.6% mortality) was driven by the poor prognosis of intracranial haemorrhage (ICH; n = 143, 65.4% mortality, model contribution 7.8%). The adjusted hazard ratios (HRs) for 30-day death for any major bleeding and for ICH were 2.9 [2.4-3.6] and 10.3 [8.2-12.8], respectively. Neither non-ICH major nor minor bleeding was associated with 30-day death after adjustment. Cardiogenic shock (HR 13.5, 61% contribution) and age (HR 1.6/decade, 17% contribution) were most strongly correlated with 30-day death. Among 30-day survivors, age (HR 1.6/decade, contribution 43%) and heart rate (HR 1.2 per 10 b.p.m., contribution 18%) were most strongly associated with mortality between Days 31 and 365.nnnCONCLUSIONnCardiogenic shock, age, and ICH were important independent correlates of 30-day and 1-year mortality in STEMI patients receiving fibrinolytic therapy. In-hospital non-ICH major and minor bleeding were not independently associated with increased mortality at 30 days or 1 year.

Baseline hemoglobin concentration and creatinine clearance composite laboratory index improves risk stratification in ST-elevation myocardial infarction

BACKGROUNDnHemoglobin (Hgb) and creatinine clearance (CrCl) are readily-available, routinely-obtained laboratory parameters that predict acute coronary syndrome outcomes. We sought to develop a laboratory index (LI) to predict early mortality in ST-elevation myocardial infarction (STEMI) and determine the additional risk stratification offered by adding the LI to the TIMI Risk Score (TRS) for STEMI.nnnMETHODS AND RESULTSnThe association between Hgb and CrCl values obtained at hospitalization and 30-day mortality was evaluated in 14,373 STEMI patients undergoing fibrinolysis in Intravenous NPA for the Treatment of Infarcting Myocardium Early II-Thrombolysis In Myocardial Infarction-17 (InTIME II-TIMI 17). Logistic regression models determined the optimal combination of laboratory variables into a LI. Prognostic utility of the LI was validated in 18,427 STEMI patients from Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)-TIMI 25. In InTIME II, Hgb levels <15.0 g/dL and CrCl <100 mL/min were significantly and independently associated with increased risk of death (OR(adj) 1.22, 95% CI 1.15-1.29 for each 1 g/dL decrease in Hgb, P < .001, and OR(adj) 1.23, 95% CI 1.17-1.29 for each 10 mL/min decrease in CrCl, P < .001, respectively). In multivariable analysis, the optimal weighting of Hgb and CrCl to form an LI to predict mortality was (15-Hgb) + (100-CrCl)/8. The LI revealed a 10-fold increase in death across prespecified groups (P < .001). The LI offered additional risk stratification across all TRS groups and improved the discriminatory ability of the TRS (c-statistic from 0.755 to 0.789, P < .001). External validation in ExTRACT showed similar enhancement of the prognostic capacity of the TRS (c-statistic from 0.747 to 0.777, P < .001).nnnCONCLUSIONSnThe LI is a simple, powerful tool to predict death in STEMI, either separately or with the TRS.

Effect of Loading Dose of Atorvastatin Prior to Planned Percutaneous Coronary Intervention on Major Adverse Cardiovascular Events in Acute Coronary Syndrome: The SECURE-PCI Randomized Clinical Trial

Importance The effects of loading doses of statins on clinical outcomes in patients with acute coronary syndrome (ACS) and planned invasive management remain uncertain. Objective To determine if periprocedural loading doses of atorvastatin decrease 30-day major adverse cardiovascular events (MACE) in patients with ACS and planned invasive management. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites in Brazil among 4191 patients with ACS evaluated with coronary angiography to proceed with a percutaneous coronary intervention (PCI) if anatomically feasible. Enrollment occurred between April 18, 2012, and October 6, 2017. Final follow-up for 30-day outcomes was on November 6, 2017. Interventions Patients were randomized to receive 2 loading doses of 80 mg of atorvastatin (nu2009=u20092087) or matching placebo (nu2009=u20092104) before and 24 hours after a planned PCI. All patients received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. Main Outcomes and Measures The primary outcome was MACE, defined as a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization through 30 days. Results Among the 4191 patients (mean age, 61.8 [SD, 11.5] years; 1085 women [25.9%]) enrolled, 4163 (99.3%) completed 30-day follow-up. A total of 2710 (64.7%) underwent PCI, 333 (8%) underwent coronary artery bypass graft surgery, and 1144 (27.3%) had exclusively medical management. At 30 days, 130 patients in the atorvastatin group (6.2%) and 149 in the placebo group (7.1%) had a MACE (absolute difference, 0.85% [95% CI, −0.70% to 2.41%]; hazard ratio, 0.88; 95% CI, 0.69-1.11; Pu2009=u2009.27). No cases of hepatic failure were reported; 3 cases of rhabdomyolysis were reported in the placebo group (0.1%) and 0 in the atorvastatin group. Conclusions and Relevance Among patients with ACS and planned invasive management with PCI, periprocedural loading doses of atorvastatin did not reduce the rate of MACE at 30 days. These findings do not support the routine use of loading doses of atorvastatin among unselected patients with ACS and intended invasive management. Trial Registration clinicaltrials.gov Identifier: NCT01448642

In Patients With Acute Myocardial Infarction, the Impact of Hyperglycemia as a Risk Factor for Mortality Is Not Homogeneous Across Age-Groups

OBJECTIVE To assess the impact of hyperglycemia in different age-groups of patients with acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS A total of 2,027 patients with AMI were categorized into one of five age-groups: <50 years (n = 301), ≥50 and <60 (n = 477), ≥60 and <70 (n = 545), ≥70 and <80 (n = 495), and ≥80 years (n = 209). Hyperglycemia was defined as initial glucose ≥115 mg/dL. RESULTS The adjusted odds ratios for hyperglycemia predicting hospital mortality in groups 1–5 were, respectively, 7.57 (P = 0.004), 3.21 (P = 0.046), 3.50 (P = 0.003), 3.20 (P < 0.001), and 2.16 (P = 0.021). The adjusted P values for correlation between glucose level (as a continuous variable) and mortality were 0.007, <0.001, 0.043, <0.001, and 0.064. The areas under the ROC curves (AUCs) were 0.785, 0.709, 0.657, 0.648, and 0.613. The AUC in group 1 was significantly higher than those in groups 3–5. CONCLUSIONS The impact of hyperglycemia as a risk factor for hospital mortality in AMI is more pronounced in younger patients.

Streptokinase and enoxaparin as an alternative to fibrin-specific lytic-based regimens: an ExTRACT-TIMI 25 analysis.

AbstractBackground: Enoxaparin was superior to unfractionated heparin (UFH), regardless of fibrinolytic agent in ST-elevation myocardial infarction (STEMI) patients receiving fibrinolytic therapy in ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction 25) trial.n Objective: This post hoc analysis compared outcomes with streptokinase plus enoxaparin to the standard regimen of fibrin-specific lytic (FSL) plus UFH and to the newer combination of FSL plus enoxaparin.n Methods: In ExTRACT-TIMI 25, STEMI patients received either streptokinase or a FSL (alteplase, reteplase or tenecteplase) at the physician’s discretion and were randomized to enoxaparin or UFH, stratified by fibrinolytic type. Thirty-day outcomes were adjusted for baseline characteristics, region, in-hospital percutaneous coronary intervention (PCI) and a propensity score for the choice of lytic.n Results: The primary trial endpoint of 30-day death/myocardial infarction (MI) occurred in fewer patients in the streptokinase-enoxaparin cohort (n = 2083) compared with FSL-UFH (n = 8141) [10.2% vs 12.0%, adjusted odds ratio [ORadj] 0.76; 95% CI 0.62, 0.93; p = 0.008]. Major bleeding was significantly increased with streptokinase-enoxaparin compared with FSL-UFH (ORadj 2.74; 95% CI 1.81; 4.14; p<0.001) but intracranial haemorrhage (ICH) was similar (ORadj 0.90; 95% CI 0.40, 2.01; p = 0.79). Net clinical outcomes, defined as either death/MI/major bleeding or as death/MI/ICH tended to favour streptokinase-enoxaparin compared with FSL-UFH (ORadj 0.88; 95% CI 0.73, 1.06; p = 0.17; and ORadj 0.77; 95% CI 0.63,0.93; p = 0.008, respectively). Patients receiving FSL-enoxaparin (n = 8142) and streptokinase-enoxaparin therapies experienced similar adjusted rates of the primary endpoint (ORadj 1.08; 95% CI 0.87, 1.32; p = 0.49) and net clinical outcomes.n Conclusions: Our results suggest that fibrinolytic therapy with the combination of streptokinase and the potent anticoagulant agent enoxaparin resulted in similar adjusted outcomes compared with more costly regimens utilizing a FSL.

Myocardial Inactivation of Thyroid Hormones in Patients with Aortic Stenosis

OBJECTIVEnThe human heart expresses the type 2 deiodinase (D2) that activates thyroxine (T4) to triiodothyronine (T3). At the same time, the inactivating type 3 deiodinase (D3) has been found in a rat model of right ventricular hypertrophy. It is not known whether the human myocardium metabolizes thyroid hormone. This study examined myocardial thyroid hormone metabolism in patients with aortic valve stenosis (AS) undergoing aortic valve replacement and in patients with coronary artery disease (CAD) undergoing coronary artery bypass grafting surgery.nnnMETHODSnMyocardial thyroid hormone metabolism was assessed by analyzing the difference in serum thyroid hormone levels between the aortic root (incoming blood) and the coronary sinus (outgoing blood) of patients undergoing cardiac surgery. A total of 23 patients with AS and 35 patients with CAD were included. Patients received a pre-surgical echocardiogram, and pre-, during and post-surgical thyroid hormone serum levels were collected in the myocardial and peripheral circulations.nnnRESULTSnPatients with AS exhibited the expected left ventricle (LV) hypertrophy (i.e., 20-30% increase in LV posterior wall and interventricular septum thickness and ∼10% increase in AS in LV diastolic diameter). Immediately before cardiopulmonary bypass, blood flowing through the AS myocardium exhibited a 4.6% reduction in T3 and 6.9% increase in rT3 levels, decreasing the serum T3/rT3 ratio by 9.6%. T4 and thyrotropin serum levels remained similar between the aortic root and coronary sinus. In contrast, no myocardial thyroid hormone metabolism was observed in CAD patients. Notably, the AS myocardium lost the ability to inactivate thyroid hormone after cardiopulmonary bypass, possibly due to myocardial stunning.nnnCONCLUSIONSnThere is accelerated thyroid hormone inactivation in the AS myocardium, which is likely the result of D3 expression. No evidence to suggest thyroid hormone activation in the myocardium was obtained in the present study.

Pseudoaneurisma de ventrículo esquerdo associado a insuficiência mitral grave complicando infarto agudo do miocárdio ínfero-látero-dorsal

We described a case of left ventricular pseudoaneurysm associated to a severe mitral regurgitation, complicating a inferolaterodorsal acute myocardial infarction. The lesion was found in a routine echocardiogram during the in-hospital follow-up. The well-succeeded surgical strategy and the good clinical evolution of the patient were distinguished.

Rationale and design of the Statins Evaluation in Coronary procedUres and REvascularization: The SECURE-PCI Trial

Background: Previous evidence suggests that acute treatment with statins reduce atherosclerotic complications, including periprocedural myocardial infarction, but currently, there are no large, adequately powered studies to define the effects of early, high‐dose statins in patients with acute coronary syndrome (ACS) and planned invasive management. Objectives: The main goal of Statins Evaluation in Coronary procedUres and REvascularization (SECURE‐PCI) Trial is to determine whether the early use of a loading dose of 80 mg of atorvastatin before an intended percutaneous coronary intervention followed by an additional dose of 80 mg 24 hours after the procedure will be able to reduce the rates of major cardiovascular events at 30 days in patients with an ACS. Design: The SECURE‐PCI study is a pragmatic, multicenter, double‐blind, placebo‐controlled randomized trial planned to enroll around 4,200 patients in 58 different sites in Brazil. The primary outcome is the rate of major cardiovascular events at 30 days defined as a composite of all‐cause mortality, nonfatal acute myocardial infarction, nonfatal stroke, and coronary revascularization. Summary: The SECURE PCI is a large randomized trial testing a strategy of early, high‐dose statin in patients with ACS and will provide important information about the acute treatment of this patient population.