Infarction Survival Research Articles

Usefulness of Abnormal Heart Rate Turbulence to Predict Cardiovascular Mortality in High-Risk Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction (from the EPHESUS Study)

Heart rate turbulence (HRT) is a promising marker for risk of mortality after acute myocardial infarction (AMI). We investigated HRT for risk stratification in high-risk patients after MI. HRT from 24-hour Holter monitoring in 481 hospitalized patients after AMI with heart failure and/or diabetes with left ventricular dysfunction before randomization in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Over a 1-year follow-up, 55 died, 49 of cardiovascular causes. HRT onset (TO) and slope (TS) were calculated using previous and cohort-optimized cutpoints and their independent contribution to risk of cardiovascular death determined. Models were tested with <5 ventricular premature complexes (PVCs) categorized as normal (n = 452) and with <5 VPCs excluded (n = 342). In EPHESUS, optimal cutpoints were TS < or = 3.0 and TO > or = 0.0. The strongest model for predicting cardiovascular mortality used EPHESUS cutpoints excluding subjects with <5 VPCs. On 3-category HRT model multivariate analysis (TS and TO normal, TS or TO abnormal, TS and TO abnormal), both TS and TO abnormal (relative risk 3.64, 95% confidence interval 1.55 to 8.55, p = 0.003) and left ventricular ejection fraction < or =30% (relative risk 1.97, 95% confidence interval 1.04 to 3.73, p = 0.037) independently predicted cardiovascular death. In conclusion, HRT is an independent predictor of cardiovascular death in a high-risk population after AMI, with a possibly higher optimal cutpoint for HRT slope than previously reported.

A History of Systemic Hypertension and Incident Heart Failure Hospitalization in Patients With Acute Myocardial Infarction and Left Ventricular Systolic Dysfunction

The associations of a history of hypertension with subsequent outcomes after acute myocardial infarction have not been examined in propensity-matched studies. Of the 6,632 patients with acute myocardial infarctions and left ventricular systolic dysfunction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), 4,407 had histories of hypertension. Propensity scores for a history of hypertension, estimated for each patient using 64 baseline characteristics, were used to match 1,990 pairs of patients with and without hypertension. Matched Cox regression models were used to estimate associations between hypertension and outcomes during a mean of 16 months of follow-up. Heart failure (HF) hospitalization occurred in 11.9% and 8.8% of patients, respectively, with and without hypertension (hazard ratio [HR] for hypertension vs no hypertension 1.36, 95% confidence interval [CI] 1.10 to 1.68, p = 0.004). The association between a history of hypertension and HF hospitalization was significant only in patients without previous HF (n = 3,495, HR 1.48, 95% CI 1.18 to 1.84, p = 0.001), but not in those with previous HF (n = 485, HR 1.09, 95% CI 0.73 to 1.62, p = 0.688, p for interaction = 0.179). A history of hypertension was not associated with all-cause mortality (HR 1.02, 95% CI 0.86 to 1.22, p = 0.790) or cardiovascular hospitalization (HR 1.08, 95% CI 0.92 to 1.27, p = 0.339). In conclusion, a history of hypertension was associated with subsequent HF hospitalization after acute myocardial infarction, especially in patients without histories of HF, suggesting that hypertension increased the risk for hospitalization with incident HF but did not affect hospitalization for worsening HF symptoms in those with prevalent HF.

On Looking at Subgroups

More than 20 years ago in this journal, Furberg and Byington1 showed how dicing a population from a randomized trial could unearth apparent subgroup findings. They used the Beta-Blocker in Heart Attack Trial, a double-blind randomized trial that showed conclusive evidence of benefit of β-blockers on mortality in patients who had experienced a myocardial infarction. In spite of this overall benefit, the authors showed that some subgroups exhibited no effect and some subgroups exhibited harm; they argued cogently that these “findings” were likely spurious. A few years later came the well-known example of spurious interaction from the International Study of Infarct Survival 2 (ISIS-2),2 a trial that showed a medically important and statistically significant benefit of aspirin in preventing fatal heart attacks. To demonstrate the pitfalls of subgroup analysis, the ISIS investigators classified all study participants by their astrological signs; subgroup analysis showed that whereas aspirin significantly benefited the population at large, it appeared actually to harm people born under Gemini or Libra. Most nonastrologers would believe the findings due to chance. Article p 922 Most randomized clinical trials aim to show an effect of an experimental treatment in a given study population. Because most illnesses are variable, it seems quite natural to look to clinical trials for information about specific subgroups of patients in the hope that subgroup-specific estimates of treatment effects, rather than the overall effect, will predict more accurately the effect on specific patients. Unfortunately, few trials have sufficient statistical power to measure reliably the effect of a treatment within subgroups. Trials are even less likely to provide reliable information on interactions, that is, whether the effect of a treatment differs among subgroups. The persistence of subgroup analyses, in spite of nearly all statisticians’ and many clinicians’ oft-stated warnings about their unreliability, must be due …

Patient Health Status and Costs in Heart Failure

Although a variety of prognostic tools have been shown to predict rehospitalization and mortality in heart failure patients, their utility in assessing future costs is less clear. We assessed whether health status assessment with the Kansas City Cardiomyopathy Questionnaire (KCCQ) predicts future costs in stable heart failure outpatients with left ventricular dysfunction after myocardial infarction. We evaluated 12-month cost utilization data from 1516 heart failure outpatients enrolled in the Quality-of-Life Substudy of the Eplerenone Post-Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Multivariable hierarchical models assessed whether the KCCQ (categorized as 0 to <25, 25 to <50, 50 to <75, and 75 to 100) was an independent predictor of future resource use. At baseline, 685 patients (45.2%) had good health status (KCCQ scores > or =75), whereas 510 (33.6%), 262 (17.3%), and 59 (3.9%) had fair (KCCQ, 50 to 74), poor (KCCQ, 25 to 49), and the worst (KCCQ <25) health status, respectively. After multivariable adjustment, compared with patients with good health status, patients with fair health status incurred incremental 1-year costs of $1520 (cost ratio, 1.23; 95% confidence interval, 1.05 to 1.43), whereas patients with poor and the worst health status incurred incremental 1-year costs of $4265 (cost ratio, 1.63; 95% confidence interval, 1.34 to 1.99) and $8999 (cost ratio, 2.34; 95% confidence interval, 1.62 to 3.38), respectively (P<0.0001 for association with KCCQ). Further adjustment for New York Heart Association class led to only partial attenuation of this relationship (P=0.0002). Health status assessment predicts resource use and costs over the next year in stable heart failure outpatients with left ventricular dysfunction after myocardial infarction.

Utility Estimates for Decision–Analytic Modeling in Chronic Heart Failure—Health States Based on New York Heart Association Classes and Number of Rehospitalizations

Objectives For economic evaluations of chronic heart failure (CHF) management strategies, utilities are not currently available for disease proxies commonly used in Markov models. Our objective was to estimate utilities for New York Heart Association (NYHA) classification and number of cardiovascular rehospitalizations. Methods EuroQol 5D data from the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study trial were used to estimate utilities as a function of NYHA classification and number of cardiovascular rehospitalizations. Results In multivariate regression analyses adjusted for age (60 years), female sex and absence of further comorbidities, utilities for NYHA classes I–IV were 0.90, 0.83, 0.74, and 0.60 ( P-value < 0.001 for trend). For cardiovascular rehospitalizations 0, 1, 2 and ≥3, the associated utilities were 0.88, 0.85, 0.84, and 0.82 ( P-value < 0.001 for trend). Conclusions NYHA class and number of cardiovascular rehospitalizations are established proxies for CHF progression and can be linked to utilities when used as health states in a Markov model. NYHA class should be used when feasible.

Understanding Stroke in Women

See related article, pages 909–914. “The pure and simple truth is rarely pure and never simple”. —Oscar Wilde Sex differences in clinical care and outcomes have been documented in multiple studies of patients with coronary artery disease, with research showing differences in presentation, disparities in diagnosis and management, and worse clinical outcomes in women compared to men.1,2 There has been concern that similar sex differences exist in the care and outcomes of patients with stroke, given the parallels in patient populations and risk factors in individuals with cardiac and cerebrovascular disease. To date, however, the research on the interaction between gender and stroke has been limited and results have been inconsistent. Thus, any new information on this topic is welcome. In this issue of Stroke , Eriksson et al3 report on an analysis of 24 633 stroke events in 2006 from the large, well-designed, population-based Swedish National Quality Register (RIKS-Stroke). They found that compared to men, women were older (mean age difference 4.8 years) and were more often unconscious on presentation. No differences were found in processes of care such as administration of thrombolysis or discharge on anticoagulants. Women were more likely to develop deep venous thromboses and fractures, whereas men …

Nonrandomized Comparison of Coronary Artery Bypass Surgery and Percutaneous Coronary Intervention for the Treatment of Unprotected Left Main Coronary Artery Disease in Octogenarians

The objective of the present study was to compare the midterm follow-up results of percutaneous coronary intervention (PCI) and coronary bypass graft surgery (CABG) for the treatment of unprotected left main coronary artery disease in octogenarians. A total of 249 consecutive patients > or =80 years of age diagnosed with left main coronary artery disease underwent coronary revascularization in our center between January 2002 and January 2008; 145 patients underwent CABG, and 104 patients had PCI. Major adverse cardiac and cerebrovascular events (MACCE [cardiac death, myocardial infarction, cerebrovascular event, revascularization]) were evaluated at a mean follow-up of 23 +/- 16 months. Patients who underwent PCI were older; had higher creatinine levels, lower ejection fraction, and higher EuroSCORE; and presented more frequently with an acute coronary syndrome. Drug-eluting stents were used in 48% of PCI patients. A propensity score analysis was performed to adjust for baseline differences between the 2 groups. Survival free of cardiac death or myocardial infarction (PCI, 65.4%; CABG, 69.7%) and MACCE-free survival (PCI, 56.7%; CABG, 64.8%) at follow-up were similar between the groups (adjusted hazard ratio for survival free of cardiac death or myocardial infarction, 1.28; 95% CI, 0.64 to 2.56; P=0.47; adjusted hazard ratio for MACCE-free survival, 1.11; 95% CI, 0.59 to 2.0; P=0.73). The EuroSCORE value was an independent predictor of MACCE regardless of the type of revascularization (hazard ratio, 1.17 for each EuroSCORE increase of 1 point; 95% CI, 1.09 to 1.25; P<0.0001). In this single-center, nonrandomized study, there were no significant differences in cardiac death or myocardial infarction and MACCE between CABG and PCI for the treatment of left main coronary artery disease in octogenarians after a mean follow-up of 2 years. Baseline EuroSCORE was the most important predictor of MACCE regardless of the type of revascularization. Randomized studies comparing both revascularization strategies in this high-risk coronary population are warranted.

Abstract 572: Hyperglycemia and Poor Outcomes in Patients without Diabetes Mellitus in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS): A Propensity Matched Analysis

Background: The effect of hyperglycemia on outcomes in patients with acute MI (AMI) and low LVEF without diabetes mellitus is not well known. Methods: In the EPHESUS trial, of the 4411 non-DM patients, 554 had baseline hyperglycemia (≥140 mg/dL). Propensity scores for hyperglycemia were calculated for each of the 4411 patients based on 63 baseline covariates, and a greedy 1:8 matching protocol was used to match 400 and 2542 patients respectively with and without hyperglycemia. Matched Cox regression models were used to estimate associations between hyperglycemia and outcomes during 16 months of follow up. Results: Patients with hyperglycemia were more likely to be older, have higher heart rate, lower LVEF, and receive nitrates, statins, digoxin, loop diuretics, and PTCA during index admission. Unadjusted hazard ratios {HR} and 95% confidence intervals {CI} for hyperglycemia were: all-cause death (1.51; 1.22–1.87; P&lt;0.001), cardiovascular (CV) death (1.52; 1.21–1.90; P&lt;0.001), heart failure (HF) death (2.19, 1.46–3.29; P&lt;0.001), all-cause hospitalization (1.23; 1.08–1.40; P=0.002), CV hospitalization (1.51, 1.24–1.84; P&lt;0.001) and HF hospitalization (1.75; 1.37–2.25; P&lt;0.001). In the matched cohort, hyperglycemia was significantly associated with CV death (HR=1.25, 95%CI=1.01–1.54; P=0.039), sudden cardiac death (HR=1.33; 95%CI=1.02–1.73, P=0.035) and fatal/nonfatal AMI (HR=1.53, 95%CI=1.07–2.19; P=0.04; Figure ). Conclusions: In non-diabetic post-AMI HF patients, hyperglycemia is a poor prognosticator and is associated with increased risk of fatal and non-fatal AMI, CV death, HF deaths, sudden cardiac death, and CV hospitalization. Figure Fatal or non fatal acute myocardial infarction (AMI) by baseline serum glucose in post-AMI patients with no known history of diabetes mellitus

Patient Satisfaction and Its Relationship With Quality and Outcomes of Care After Acute Myocardial Infarction

Patient satisfaction is a widely used measurement for the evaluation of medical care. We examined the extent to which quality of care received after acute myocardial infarction predicted subsequent patient satisfaction with care and whether patient satisfaction itself was associated with long-term survival after acute myocardial infarction. In a longitudinal cohort of acute myocardial infarction, we examined the associations of patient-reported satisfaction with care with clinical characteristics, physical and psychological function measures, quality indicators of myocardial infarction care, and outcomes. Among 1933 eligible patients (mean age 62.9+/-12.8 years, 70.5% men), 1866 survey respondents were analyzed. Of the study cohort, 1711 (91.7%) reported that they were satisfied with their overall care. Patients who reported satisfaction with care were older (mean age 63.1+/-12.7 versus 60.1+/-13.3 years, P=0.005), had improved physical function, and were less likely to be depressed. Better physical function, measured by the Specific Activity Scale, predicted higher satisfaction, with an OR of 1.75 (95% CI 1.17 to 2.68, P=0.008) for intermediate versus poor function and 2.96 (1.39 to 7.34, P=0.009) for high versus poor function, after adjustment for age, sex, income tertile, and ethnicity. Depression was the major predictor of dissatisfaction with overall care, with an OR of 0.44 (95% CI 0.29 to 0.67, P<0.001). Quality indicators for myocardial infarction care and clinical outcomes were not associated with patient satisfaction. Satisfaction with care was more likely in patients who were older, in those without depression, and in those with better functional capacity, but it was not associated with the quality of myocardial infarction care or survival.

Therapy of Acute Basilar Artery Occlusion

While intravenous recombinant tissue plasminogen activator (rt-PA) has been approved for acute stroke therapy within 3 hours, the optimum management of basilar artery occlusion (BAO) is still a matter of debate. We compared intraarterial thrombolysis with the combined bridging approach of intravenous abciximab and intraarterial thrombolysis with rt-PA (bridging therapy) in an observational, longitudinal, monocenter study. Between 1998 and 2006, information for 106 patients with acute BAO were prospectively entered into a local database. Patients eligible for treatment received either intraarterial thrombolysis with rt-PA alone (intraarterial thrombolysis) or were treated with intravenous abciximab and intraarterial rt-PA (bridging therapy). Outcome parameters were recanalization of the basilar artery according to Trial in Myocardial Infarction criteria, survival, and reduction of severe disability and death at 3 months. Logistic regression was used to identify independent predictors for recanalization, survival, and clinical outcome. Of a total of 106 patients with confirmed BAO, 87 patients underwent subsequent angiography. Among those, 75 patients were identified who received the full treatment protocol. Patients in the bridging group had a better recanalization rate (83.7% vs 62.5%; P=0.03), a higher survival rate (58.1% vs 25%; P=0.01), and a better chance for an outcome with no or only mild to moderate disability (modified Rankin Scale score, 0-3; 34.9% vs 12.5%; P=0.02). Symptomatic intracerebral hemorrhage rates were comparable in both groups (14% in the bridging group vs 18.8%; P=0.41). Independent predictors for recanalization were age (OR, 0.95; 95% CI, 0.91-0.99), atrial fibrillation (OR, 6.53; 95% CI, 1.14-37.49), and bridging therapy (OR, 3.37; 95% CI, 1.02 to 11.18). Independent prognostic factors for outcome were Glasgow coma scale score at presentation (OR, 1.24; 95% CI, 1.03-1.45) and the combination of bridging therapy with successful recanalization (OR, 3.744; 95% CI, 1.04-13.43). Bridging therapy for acute BAO with intravenous abciximab and intraarterial rt-PA appears to be safe and yields higher recanalization and improved survival rates, as well as an overall improved chance for a better outcome.

Clinical Summaries

Clinical Summaries

Kallikrein teams up with GSK-3 in heart failure prevention

With heart failure becoming an increasing burden due to the ageing population and improved peri-myocardial infarct (MI) survival, therapeutic approaches to stop or even revert this pathological process are gaining increasing attention. A most promising approach for the therapy is considered to rapidly increase blood supply to the damaged post-infarction ischaemic tissue in an attempt to limit cardiomyocyte death, thereby limiting scarring and its ensuing development of myocardial failure. Many experimental approaches have used growth factor induction, either as proteins or as DNA vectors, in an attempt to increase the local blood supply via induction of an improved capillary bed by angiogenesis or, even better, to induce increased collateral development by arteriogenesis.1 This field of therapeutic angiogenesis was sparked by the breakthrough paper of the Isner laboratory, showing improved perfusion in the ischaemic diabetic leg after vascular endothelial growth factor (VEGF) gene therapy.2 Multiple strategies that proved to be highly promising in animal models of ischaemic hindlimb after femoral artery occlusion were also tested in a myocardial setting. Almost a decade later, however, the original enthusiasm for the growth factor therapy has faded based on disappointing results in large clinical trials.3,4 The underlying … *Corresponding author. Tel: +31 20 4448161; fax: +31 20 4448081. E-mail address: aj.horrevoets{at}vumc.nl

Serum Potassium and Clinical Outcomes in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

Aldosterone blockade is recommended for patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction; however, the perceived risk of hyperkalemia may limit implementation of this therapeutic approach. This subanalysis examined the relationship between eplerenone, serum potassium (K(+)), and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Hospitalized patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction (left ventricular ejection fraction < or =40%) treated with standard therapy were randomized 3 to 14 days after the acute myocardial infarction to additional treatment with eplerenone (25 to 50 mg/d; n=3319) or placebo (n=3313). Patients were excluded if baseline K(+) was >5.0 mEq/L or serum creatinine was >2.5 mg/dL. In patients receiving standard therapy, the addition of eplerenone resulted in a 4.4% absolute increase in the incidence of K(+) >5.5 mEq/L, a 1.6% increase of K(+) > or =6.0 mEq/L, and a 4.7% absolute decrease in hypokalemia (K(+) <3.5 mEq/L). Four independent baseline predictors of hyperkalemia (defined as > or =6.0 mEq/L) were identified: potassium (K(+) greater than the median; 4.3 mEq/L), estimated glomerular filtration rate (< or =60 mL . min(-1) . 1.73 m(-2)), history of diabetes mellitus, and prior use of antiarrhythmic agents. None of these independent baseline risk factors significantly impacted the cardiovascular benefit of eplerenone for reducing all-cause mortality. Use of selective aldosterone blockade with eplerenone within the dose range of 25 to 50 mg/d in post-acute myocardial infarction patients with heart failure and left ventricular systolic dysfunction who are treated with standard therapy improves outcomes without an excess of risk of hyperkalemia (> or =6.0 mEq/L) when periodic monitoring of serum K(+) is instituted.

Cost-effectiveness analysis of aldosterone blockade with eplerenone in patients with heart failure after acute myocardial infarction in the French context: The EPHESUS study

The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) randomized clinical trial demonstrated the efficacy of eplerenone, a new aldosterone antagonist diuretic, with standard treatment versus standard treatment alone in the reduction of cardiovascular mortality and cardiovascular-related hospital readmissions for patients with heart failure after an acute myocardial infarction. We assessed the incremental cost per life-year saved of eplerenone in the French context versus standard treatment. A within-trial study was designed. A piecewise regression model yielded death rates and survival gains adjusted for patients' characteristics, based on the extraction of comparable patients from the Saskatchewan Health database. Resource use was collected alongside the clinical trial data. Only direct medical costs were considered. All costs were in 2003 euros. Costs and outcomes were discounted at 5%. The overall mortality rate was 14.4% in the treatment group versus 16.7% in the placebo group (p=0.008). Combined cardiovascular deaths and hospitalization rates were 26.7% in the treatment group versus 30.3% in the placebo group (p=0.002). The discounted survival gain was 3.2 weeks. The incremental cost per life-year saved was euro15,382 (95% confidence interval 8274-42,723). Seventy-four per cent of the values of the incremental cost-effectiveness ratio fell under a euro15,000 per life-year saved threshold. The cost of eplerenone leads to an acceptable level of incremental cost per life-year saved when compared with existing treatments in the cardiovascular domain for the prevention of cardiovascular death and morbidity in patients with heart failure after an acute myocardial infarction.

Cardiovascular Risk and α-Linolenic Acid

Interest is increasing in the potential cardioprotective role of ω-3 (n-3) fatty acids (FAs). Most of the evidence supporting this hypothesis has been derived from studies of the longer-chain members of the n-3 family, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in fish oils.1 The value of the shorter-chain cousin, α-linolenic acid (ALA), found in certain plant oils (flaxseed, soybean, canola, walnut) has been less clear.2 If ALA were able to do the same “heavy lifting” that EPA and DHA do, this would be welcomed news because the capacity to produce ALA is essentially limitless, whereas there are only so many fish in the sea. Campos and colleagues report in this issue of Circulation the results of a major study conducted in Costa Rica that provided new evidence that higher ALA intakes are associated with reduced risk for nonfatal myocardial infarction.3 Article p 339 Three weeks after surviving a heart attack, 1819 patients provided an adipose tissue biopsy for analysis of FA stores and completed a validated food frequency questionnaire. A similar number of matching controls did the same. The authors reported a strong inverse association between myocardial infarction case status and ALA tissue levels across the range of 0.4% to 1% of total adipose tissue FAs, and this corresponded to intakes between 0.4% and 0.9% of total energy (or 1 to 2.4 g ALA per day). This is remarkably …

Blocking pterygopalatine arterial blood flow decreases infarct volume variability in a mouse model of intraluminal suture middle cerebral artery occlusion

The mouse model of intraluminal suture middle cerebral artery occlusion (MCAO) is still associated with several issues, such as variability of infarction volume and survival. Thus, the method is far from standardization. The effect of blood flow in the pterygopalatine artery (PPA) in the mouse MCAO model remains obscure. While producing mouse MCAO models using commercially available silicone-coated monofilaments, we temporarily occluded the common carotid artery (CCA) or PPA to determine whether cerebral blood flow (CBF) values, infarct size and the stability of the model would be affected. Forty male C57BL/6 mice were divided into 3 groups: MCAO with blocked CCA blood flow (MCAO-C; n=12), MCAO with blocked PPA blood flow (MCAO-P; n=16) and MCAO without either CCA or PPA blood flow blockage (MCAO-U; n=12). We found that the CBF values were significantly higher during occlusion in the MCAO-U than in the other two groups (p<0.001). We stained whole brains from each group at 24h after reperfusion with 2% 2,3,5-triphenyltetrazolium chloride. Although mean infarct volume did not obviously differ between the MCAO-U and other two groups, infarct volumes varied significantly more within the MCAO-U, than in the other two groups (p<0.05). We concluded that collateral circulation from the PPA to the brain significantly influences the MCAO model, and cannot be ignored. An approximately consistent mouse MCAO model can be generated using commercially available silicone-coated sutures while blocking PPA blood flow during occlusion.

History of Hypertension and Eplerenone in Patients With Acute Myocardial Infarction Complicated by Heart Failure

In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (n=6632), eplerenone-associated reduction in all-cause mortality was significantly greater in those with a history of hypertension (Hx-HTN). There were 4007 patients with Hx-HTN (eplerenone: n=1983) and 2625 patients without Hx-HTN (eplerenone: n=1336). Propensity scores for eplerenone use, separately calculated for patients with and without Hx-HTN, were used to assemble matched cohorts of 1838 and 1176 pairs of patients. In patients with Hx-HTN, all-cause mortality occurred in 18% of patients treated with placebo (rate, 1430/10 000 person-years) and 14% of patients treated with eplerenone (rate, 1058/10 000 person-years) during 2350 and 2457 years of follow-up, respectively (hazard ratio [HR]: 0.71; 95% CI: 0.59 to 0.85; P<0.0001). Composite end point of cardiovascular hospitalization or cardiovascular mortality occurred in 33% of placebo-treated patients (3029/10 000 person-years) and 28% of eplerenone-treated patients (2438/10 000 person-years) with Hx-HTN (HR: 0.82; 95% CI: 0.72 to 0.94; P=0.003). In patients without Hx-HTN, eplerenone reduced heart failure hospitalization (HR: 73; 95% CI: 0.55 to 0.97; P=0.028) but had no effect on mortality (HR: 0.91; 95% CI: 0.72 to 1.15; P=0.435) or on the composite end point (HR: 0.91; 95% CI: 0.76 to 1.10; P=0.331). Eplerenone should, therefore, be prescribed to all of the post-acute myocardial infarction patients with reduced left ventricular ejection fraction and heart failure regardless of Hx-HTN.

Not only after myocardial infarction

To the editor: We read with interest the study by Norhammar et al 1 describing the treatment and myocardial infarction survival rates according to the presence of diabetes. In their...

Optimizing care of heart failure after acute MI with an aldosterone receptor antagonist

The presence of heart failure or left ventricular systolic dysfunction in the setting of acute myocardial infarction is associated with poor prognosis. Aldosterone is an important downstream mediator of the renin-angiotensin-aldosterone system that promotes myocardial collagen deposition, myocardial fibrosis, apoptosis, ventricular remodeling, and endothelial dysfunction. It may play an important role in the increased morbidity and mortality and the development and progression of heart failure after acute myocardial infarction. Extending the findings from the Randomized Aldactone Evaluation Study (RALES) in patients with chronic heart failure, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone offered a significant survival benefit, attenuation of progression of heart failure, and prevention of sudden cardiac death when used in addition to optimal medical therapy. The current evidence-based guidelines now suggest that aldosterone blockade should be an integral component of heart failure therapy to improve outcomes in this high-risk population.

The Transforming Growth Factor-β/Smad3 Pathway

Myocardial infarction (MI) is followed by a well-described sequence of events known as postinfarction ventricular remodeling, a process that involves both the infarct scar itself and the residual surviving myocardium.1 The net results of infarct remodeling are changes in chamber size, function, and geometry. Furthermore, the remodeled ventricle becomes a substrate for both heart failure and sudden cardiac death. The elements of post-MI remodeling include infarct expansion, neurohormonal activation, myocardial hypertrophy, myocardial fibrosis, and cellular apoptosis. Article p 2127 These are linked physiological responses that attempt to compensate for the sudden decrease in contractility resulting from acute myocardial cell death.2 Infarct expansion is the thinning of the infarcted segment from slippage and stretching of myocytes and cell rupture. It is highly influenced by hemodynamic loading conditions.3 The prototypic pathways that participate in post-MI remodeling include the autonomic nervous system and renin-angiotensin-aldosterone system, which may be an attempt to maintain blood pressure and cardiac output.4 Over time, however, elevated adrenergic activity may lead to further myocardial cell loss from apoptosis,5 and both adrenergic and renin-angiotensin-aldosterone system upregulation have an adverse impact on cardiac hemodynamics. Myocardial hypertrophy, fibrosis, and apoptosis are primarily seen in the noninfarcted regions of the heart, particularly within the peri-infarct zones.2,6–8 Hypertrophy occurs in response to the increased workload for the surviving myocardiocytes, especially under suboptimal hemodynamic conditions. Myocardial hypertrophy, fibrosis, and apoptosis in the noninfarcted regions are believed to result, in part, from the neurohormonal activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and cytokine cascades. The effect of these processes is to further compound the myocardial damage sustained during the initial acute injury. The end result of these remodeling responses is global ventricular dilatation, which is a significant predictor of dysfunction and future mortality.9 Understanding the components of remodeling …