Acute coronary syndromes: identifying the appropriate patient for prasugrel.

Acute coronary syndrome (ACS) remains the leading cause of morbidity and mortality. More than half of patients presenting with ACS will experience a recurrent ischemic event; thus, preventing recurrent events is essential to reduce morbidity and mortality associated with ACS. While dual antiplatelet therapy with aspirin and clopidogrel has been the foundation of management for patients presenting with ACS, clopidogrel is limited by delayed antiplatelet effect and a variable patient response. Prasugrel is more potent, has a more rapid and consistent antiplatelet effect, and has been associated with improved outcomes compared with clopidogrel in select patients with ACS. Although prasugrel reduces the risk of recurrent cardiovascular events, it also increases the risk of major bleeding. Careful patient selection will improve the likelihood that patients treated with prasugrel will experience the benefit of this antiplatelet agent with the lowest possible risk of an adverse event. This article reviews the data supporting the use of prasugrel in ACS with an emphasis on characteristics that will help identify the most appropriate patient for this therapy.

Association of hospital primary angioplasty volume in ST-segment elevation myocardial infarction with quality and outcomes.

CONTEXT: Earlier studies indicate an inverse relationship between hospital volume and mortality after primary angioplasty for patients presenting with ST-segment elevation myocardial infarction (STEMI). However, contemporary data are lacking. OBJECTIVE: To assess the relationship between hospital primary angioplasty volume and outcomes and quality of care measures in patients presenting with STEMI. DESIGN, SETTING, AND PATIENTS: An observational analysis of data on 29,513 patients presenting with STEMI and undergoing primary angioplasty in the American Heart Association's Get With the Guidelines registry. Patients were treated between July 5, 2001, and December 31, 2007, at 166 angioplasty-capable hospitals across the United States. Hospitals were divided into tertiles (<36 procedures per year, 36-70 procedures per year, and >70 procedures per year) based on their annual primary angioplasty volume. MAIN OUTCOME MEASURES: Door-to-balloon (DTB) times, length of hospital stay, adherence with evidence-based quality of care measures, and in-hospital mortality. RESULTS: Compared with low- and medium-volume centers, high-volume centers had better median DTB times (98 vs 90 vs 88 minutes, respectively; P for trend < .001). High-volume centers were more likely than low-volume centers to follow evidence-based guidelines at discharge. Length of stay was similar between the 3 groups (P for trend = .13). There was no significant difference in the crude mortality between the tertiles of volume (incidence rate, 3.9% vs 3.2% vs 3.0% for low-, medium-, and high-volume centers, respectively; P = .26 and P = .99 for low- and medium- vs high-volume hospitals, respectively). Sequential multivariable modeling using generalized estimating equations revealed no significant association between hospital primary angioplasty volume and in-hospital mortality (adjusted odds ratio [OR], 1.22; 95% confidence interval [CI], 0.78-1.91; P = .38 and adjusted OR, 1.14; 95% CI, 0.78-1.66; P = .49 for low- and medium- vs high-volume hospitals, respectively). CONCLUSION: In a contemporary registry of patients with STEMI, higher-volume primary angioplasty centers vs lower-volume centers were associated with shorter DTB times and more use of evidence-based therapies, but not with adjusted in-hospital mortality or length of hospital stay.

The association between early ventricular arrhythmias, renin-angiotensin-aldosterone system antagonism, and mortality in patients with ST-segment-elevation myocardial infarction: Insights from Global Use of Strategies to Open coronary arteries (GUSTO) V.

BACKGROUND: The long-term prognostic significance of early (<48 hours) ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) in patients with an acute myocardial infarction remains controversial. Emerging data suggest that some of the benefit of renin-angiotensin-aldosterone system (RAAS) antagonism may be derived from a reduction in the incidence of these arrhythmias in the setting of acute myocardial infarction. METHODS: We assessed the relationship between early VF/VT (defined as within 48 hours after admission) and mortality in 16,588 patients from global use of strategies to open coronary arteries (GUSTO) V trial. Furthermore, we examined the relationship between baseline use of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), early VF/VT, and mortality. RESULTS: Early VF or VT occurred in 732 (4.4%) patients. Compared to patients without VF/VT, those experiencing early VF or VT had a significant increase in 30-day mortality (22% vs 5%, P < .001). Baseline use of an ACEI/ARB was associated with a decreased incidence of early VF/VT (odds ratio 0.65, 0.47-0.89, P = .008). A lower 30-day mortality was seen in patients with early VF/VT on baseline ACEI/ARB compared with patients with early VF/VT not receiving an ACEI/ARB at baseline (17.7% vs 24.2%, respectively, P = .04). The association between baseline RAAS antagonism and mortality persisted after adjustment for multiple confounders. CONCLUSIONS: In patients presenting with acute myocardial infarction, early VF/VT identifies those at increased risk for 30-day mortality. Baseline use of RAAS antagonists is associated with a reduced incidence of malignant arrhythmias. Identifying how this association impacts short-term mortality in this patient population requires further prospective evaluation.

Characterization of post-operative risk associated with prior drug-eluting stent use.

OBJECTIVES: The aim of this study was to assess risk of inpatient surgery at any time after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). BACKGROUND: Risk of adverse events, including stent thrombosis (ST), in patients undergoing surgical procedures with prior DES remains poorly defined. METHODS: Outcomes of consecutive patients having inpatient surgical procedures after PCI with DES, placed from April 28, 2003 until December 31, 2006 at a tertiary-care medical center, were studied. Primary and secondary end points were 30-day post-operative risk of the Academic Research Consortium (ARC) definite and modified probable definitions of ST and combined 30-day post-operative risk of death, nonfatal myocardial infarction (MI), or ST, respectively. Multivariable logistic regression analyses were used to determine independent risk factors. RESULTS: Six hundred six inpatient surgeries on 481 patients with a mean time from PCI to surgery of 1.07 +/- 0.89 years were evaluated. The primary and secondary end points occurred after 11 (2.0%) and 56 (9%) surgeries, respectively. Risk of the combined end point and ST decreased significantly in the first 1 to 6 months after PCI (p < 0.0001 and p < 0.014, respectively); however, risk persisted when time between PCI and surgery was >12 months. Independent correlates of the combined end point include emergency surgery, antecedent MI, the pre-operative use of intravenous heparin, and atherosclerotic lesion length treated with DES. Oral antiplatelet status at time of surgery was not a correlate of events. CONCLUSIONS: Risk of 30-day post-operative adverse events, including ST, remains significantly higher when surgery is performed soon after PCI, while intermediate-term risk extending at least 2 to 3 years remains important.

Long-term benefit of statin therapy initiated during hospitalization for an acute coronary syndrome: a systematic review of randomized trials.

OBJECTIVE: This study sought to determine if the initiation of statin (HMG-CoA reductase inhibitor) therapy during acute coronary syndromes reduces long-term mortality and other adverse cardiac outcomes. BACKGROUND: Initiation of statin therapy during acute coronary syndromes has not been shown to reduce mortality, myocardial infarction or stroke within 4 months of follow-up. METHODS: Clinical trials that randomized patients with acute coronary syndromes to early statin therapy compared with less intensive lipid reduction (placebo/lower-dose statin/usual care), and reported long-term outcomes were included for analysis. RESULTS: In all, there were seven studies (L-CAD, PTT, FLORIDA, Colivicchi et al., PROVE-IT, ESTABLISH, and A-to-Z) with 9553 patients who started statin therapy within 12 days of hospital presentation. The incidence of all-cause mortality was 3.4% in the statin group versus 4.6% in the less intensive lipid reduction group over a weighted mean follow-up of 22.9 months (relative risk [RR] 0.74; 95% CI 0.61, 0.90; p = 0.003). The number of patients needed to treat to prevent one death was 84 patients. Similarly, the incidence of cardiovascular mortality in the statin versus the less intensive lipid reduction group was 2.4% versus 3.3% (RR 0.74; 95% CI 0.58, 0.93; p = 0.010), unstable angina 4.1% versus 5.0% (RR 0.81; 95% CI 0.68, 0.98; p = 0.027), revascularization 11.2% versus 12.9% (RR 0.86; 95% CI 0.78, 0.96; p = 0.006), stroke 1.1% versus 1.2% (RR 0.90; 95% CI 0.62, 1.30; p = 0.56), and myocardial infarction 6.6% versus 7.0% (RR 0.94; 95% CI 0.81, 1.09; p = 0.41). CONCLUSIONS: The benefit of early initiation of statin therapy during acute coronary syndromes slowly accrues over time so that a survival advantage is seen around 24 months. Relatively few patients need to be treated to prevent one death over this time period. Furthermore, this approach significantly reduces unstable angina and the need for revascularization.

SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction.

Stem cell transplantation at the time of acute myocardial infarction (AMI) improves cardiac function. Whether the improved cardiac function results from regeneration of cardiac myocytes, modulation of remodeling, or preservation of injured tissue through paracrine mechanisms is actively debated. Because no specific stem cell population has been shown to be optimal, we investigated whether the benefit of stem cell transplantation could be attributed to a trophic effect on injured myocardium. Mesenchymal stem cells secrete SDF-1 and the interaction of SDF-1 with its receptor, CXCR4, increases survival of progenitor cells. Therefore, we compared the effects of MSC and MSC engineered to overexpress SDF-1 on cardiac function after AMI. Tail vein infusion of syngeneic MSC and MSC:SDF-1 1 day after AMI in the Lewis rat led to improved cardiac function by echocardiography by 70.7% and 238.8%, respectively, compared with saline controls 5 wk later. The beneficial effects of MSC and MSC:SDF-1 transplantation were mediated primarily through preservation, not regeneration of cardiac myocytes within the infarct zone. The direct effect of SDF-1 on cardiac myocytes was due to the observation that, between 24 and 48 h after AMI, SDF-1-expressing MSC increased cardiac myocyte survival, vascular density (18.2+/-4.0 vs. 7.6+/-2.3 vessels/mm2, P<0.01; SDF-1:MSC vs. MSC), and cardiac myosin-positive area (MSC: 49.5%; mSC:SDF-1: 162.1%) within the infarct zone. There was no evidence of cardiac regeneration by the infused MSC or endogenous cardiac stem cells based on lack of evidence for cardiac myocytes being derived from replicating cells. These results indicate that stem cell transplantation may have significant beneficial effects on injured organ function independent of tissue regeneration and identify SDF-1:CXCR4 binding as a novel target for myocardial preservation.

Redefining risk in acute coronary syndromes using molecular medicine.

Acute coronary syndromes represent a complex phenotype involving the interplay of many elements. The risk of developing an acute coronary syndrome and related complications has been defined by variables such as age, diabetes, smoking history, serum creatine phosphokinase, or electrocardiographic findings. However, in the past 5 years the wide-scale acceptance of a protein--troponin--has changed the diagnostic profile. With advances in molecular medicine, this protein is a segue to a panel of molecular assays that will improve screening and tailored intervention. We expound upon some of these factors and the potential they may carry in changing clinical medicine.

Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials.

OBJECTIVES: This study sought to systematically determine whether early invasive therapy improves survival and reduces adverse cardiovascular events in the management of non-ST-segment elevation acute coronary syndromes. BACKGROUND: Although early invasive therapy reduces recurrent unstable angina, the magnitude of benefit on other important adverse outcomes is unknown. METHODS: Clinical trials that randomized non-ST-segment elevation acute coronary syndrome patients to early invasive therapy versus a more conservative approach were included for analysis. RESULTS: In all there were 7 trials with 8,375 patients available for analysis. At a mean follow-up of 2 years, the incidence of all-cause mortality was 4.9% in the early invasive group, compared with 6.5% in the conservative group (risk ratio [RR] = 0.75, 95% confidence interval [CI] 0.63 to 0.90, p = 0.001), and at 1 month (RR = 0.82, 95% CI 0.50 to 1.34, p = 0.43). At 2 years of follow-up, the incidence of nonfatal myocardial infarction was 7.6% in the invasive group, versus 9.1% in the conservative group (RR = 0.83, 95% CI 0.72 to 0.96, p = 0.012), and at 1 month (RR = 0.93, 95% CI 0.73 to 1.19, p = 0.57). At a mean of 13 months of follow-up, there was a reduction in rehospitalization for unstable angina (RR = 0.69, 95% CI 0.65 to 0.74, p < 0.0001). CONCLUSIONS: Managing non-ST-segment elevation acute coronary syndromes by early invasive therapy improves long-term survival and reduces late myocardial infarction and rehospitalization for unstable angina.

Eptifibatide-induced thrombocytopenia and thrombosis.

Glycoprotein (GP) IIb/IIIa inhibitors have been shown to reduce morbidity and mortality in patients with acute coronary syndromes undergoing percutaneous coronary interventions (PCI). With their widespread use, there is a growing body of literature describing adverse outcomes, including severe thrombocytopenia. Here we report a case of a 75-year-old man who presented with an ST-elevation myocardial infarction, underwent primary PCI and stenting, and subsequently developed profound thrombocytopenia and thrombosis after eptifibatide administration. This report adds to the literature regarding eptifibatide-induced thrombocytopenia and also raises the possibility of a new syndrome of eptifibatide-induced thrombosis. A case is made to examine available databases for thrombosis after administration of eptifibatide and other GPIIb/IIIa inhibitors.

The double jeopardy of blunt chest trauma: a case report and review.

Cardiac injury, specifically valvular rupture, must be considered after blunt chest trauma even in previously healthy patients. Isolated mitral regurgitation (MR) and tricuspid regurgitation (TR) due to blunt chest trauma are rare phenomena. More unique is simultaneous complete papillary muscle rupture of the mitral valve (MV) and tricuspid valve (TV) with only four patients being previously reported in the literature. This case describes a patient with complete transection of the posteromedial papillary muscle of the MV with severe MR and a concomitant flail TV with severe TR following a motor vehicular accident. The importance of transthoracic and transesophageal echocardiography in the early evaluation of patients following blunt chest trauma is also highlighted by this case.

Double jeopardy of renal insufficiency and anemia in patients undergoing percutaneous coronary interventions.

Anemia and renal insufficiency impart an increased risk of mortality in patients with congestive heart failure. There is a paucity of data on the mortality hazard associated with anemia and renal insufficiency in patients undergoing percutaneous coronary intervention in the setting of contemporary practice. We analyzed the short- and long-term outcomes among patients enrolled in EPIC, EPILOG and EPISTENT trials according to degree of kidney dysfunction (glomerular filtration rate [GFR] <60, 60 to 75, and >75 ml/min/1.73 m2) and by hematocrit (<35, 35 to 39 and 40). GFR was calculated as GFR = 186 x (serum creatinine-1.154) x (age-0.203) x 1.212 (if black) or x 0.742 (if female). There were 20 deaths (3.2%) among 638 patients with a hematocrit of <35, 41 deaths among 2,066 patients (2.0%) with a hematocrit of 35 to 39, and 43 deaths in 3,618 patients (1.2%) with a hematocrit >40 at 6 months (p <0.001). Similarly, a significant increase in mortality was seen with lower GFR [33 of 1,168 (2.9%) at GFR <60, 33 of 1,766 (1.9%) at GFR 60 to 75 and 37 of 3,317 (1.1%) at GFR >75, p <0.001)]. Further, GFR and anemia independently and in combination predicted mortality at 3 years. Thus, renal insufficiency and anemia are significant independent and additive predictors of short- and long-term complications in patients undergoing percutaneous coronary intervention.

Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy.

BACKGROUND: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. METHODS: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. FINDINGS: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). INTERPRETATION: These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

Myeloperoxidase and plasminogen activator inhibitor 1 play a central role in ventricular remodeling after myocardial infarction.

Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV dilation, a major cause of congestive heart failure and sudden cardiac death. Ischemic injury and the ensuing inflammatory response participate in LV remodeling, leading to myocardial rupture and LV dilation. Myeloperoxidase (MPO), which accumulates in the infarct zone, is released from neutrophils and monocytes leading to the formation of reactive chlorinating species capable of oxidizing proteins and altering biological function. We studied acute myocardial infarction (AMI) in a chronic coronary artery ligation model in MPO null mice (MPO(-/-)). MPO(-/-) demonstrated decreased leukocyte infiltration, significant reduction in LV dilation, and marked preservation of LV function. The mechanism appears to be due to decreased oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1) in the MPO(-/-), leading to decreased tissue plasmin activity. MPO and PAI-1 are shown to have a critical role in the LV response immediately after MI, as demonstrated by markedly delayed myocardial rupture in the MPO(-/-) and accelerated rupture in the PAI-1(-/-). These data offer a mechanistic link between inflammation and LV remodeling by demonstrating a heretofore unrecognized role for MPO and PAI-1 in orchestrating the myocardial response to AMI.

Stromal cell-derived factor-1 mediates stem cell homing and tissue regeneration.

Extract: The search for alternative treatments for congestive heart failure remains an ongoing venture. Exciting research over the last 2 years has changed the long held dogma that the heart cannot regenerate itself. The work of many groups can be summarized by the following concept: increasing the number of CD117+ (c-kit+) stem cells in cardiac tissue or in the coronary circulation within 2 days of a myocardial infarction results in regeneration of myocardial tissue and improved cardiac function. Animal studies by Orlic, Anversa and colleagues have demonstrated that either the direct injection of bone marrow-derived CD117+ stem cells in the infarct border zone at the time of myocardial infarction, or mobilization of these stem cells prior to myocardial infarction results in regeneration of cardiac myocytes and improved left ventricular (LV) function. In a critical experiment, Itescu and colleagues extended the window of therapeutic opportunity by demonstrating that the intravenous infusion of bone marrow-derived stem cells 2 days after myocardial infarction led to decreased infarct size, increased vascular density and improved left ventricular function.

GUSTO V: combination drug treatment of acute myocardial infarction. Global Use of Strategies to Open Occluded Coronary Arteries.

The combination of abciximab in full doses and reteplase in half doses did not significantly reduce the rate of mortality at 30 days in patients with acute ST-segment elevation myocardial infarction (MI) when compared with reteplase in full doses in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO V) trial. However, subgroup analysis indicates that the combined regimen reduced the complications of acute MI, representing an important alternative strategy for pharmacologic reperfusion.