Showing papers by "Marc A. Pfeffer published in 2004"
TL;DR: Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen.
Abstract: background Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. methods We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24). results The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan–Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen. conclusions Among patients who have recently had an acute coronary syndrome, an intensive lipidlowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.
4,203 citations
TL;DR: Even mild renal disease, as assessed by the estimated GFR, should be considered a major risk factor for cardiovascular complications after a myocardial infarction.
Abstract: Background The presence of coexisting conditions has a substantial effect on the outcome of acute myocardial infarction. Renal failure is associated with one of the highest risks, but the influence of milder degrees of renal impairment is less well defined. Methods As part of the Valsartan in Acute Myocardial Infarction Trial (VALIANT), we identified 14,527 patients with acute myocardial infarction complicated by clinical or radiologic signs of heart failure, left ventricular dysfunction, or both, and a documented serum creatinine measurement. Patients were randomly assigned to receive captopril, valsartan, or both. The glomerular filtration rate (GFR) was estimated by means of the four-component Modification of Diet in Renal Disease equation, and the patients were grouped according to their estimated GFR. We used a 70-candidate variable model to adjust and compare overall mortality and composite cardiovascular events among four GFR groups. Results The distribution of estimated GFR was wide and normally s...
1,863 citations
TL;DR: Among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events and the trial did not achieve the prespecified end point.
Abstract: ContextLimited data are available evaluating how the timing and intensity of
statin therapy following an acute coronary syndrome (ACS) event affect clinical
outcome.ObjectiveTo compare early initiation of an intensive statin regimen with delayed
initiation of a less intensive regimen in patients with ACS.Design, Setting, and ParticipantsInternational, randomized, double-blind trial of patients with ACS receiving
40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265)
compared with ACS patients receiving placebo for 4 months followed by 20 mg/d
of simvastatin (n = 2232), who were enrolled in phase Z of the A to Z trial
between December 29, 1999, and January 6, 2003.Main Outcome MeasureThe primary end point was a composite of cardiovascular death, nonfatal
myocardial infarction, readmission for ACS, and stroke. Follow-up was for
at least 6 months and up to 24 months.ResultsAmong the patients in the placebo plus simvastatin group, the median
low-density lipoprotein (LDL) cholesterol level achieved while taking placebo
was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8
months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin
only group, the median LDL cholesterol level achieved at 1 month while taking
40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L)
at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%)
in the placebo plus simvastatin group experienced the primary end point compared
with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio
[HR], 0.89; 95% confidence interval [CI] 0.76-1.04; P =
.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) patients in
the 2 groups (HR, 0.75; 95% CI, 0.57-1.00; P = .05)
but no differences were observed in other individual components of the primary
end point. No difference was evident during the first 4 months between the
groups for the primary end point (HR, 1.01; 95% CI, 0.83-1.25; P = .89), but from 4 months through the end of the study the primary
end point was significantly reduced in the simvastatin only group (HR, 0.75;
95% CI, 0.60-0.95; P = .02). Myopathy (creatine kinase
>10 times the upper limit of normal associated with muscle symptoms) occurred
in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving
lower doses of simvastatin, and in 1 patient receiving placebo (P = .02).ConclusionsThe trial did not achieve the prespecified end point. However, among
patients with ACS, the early initiation of an aggressive simvastatin regimen
resulted in a favorable trend toward reduction of major cardiovascular events.Published online August 30, 2004 (doi:10.1001/jama.292.11.1307).
1,312 citations
TL;DR: In patients with stable coronary heart disease and preserved left ventricular function who are receiving "current standard" therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors, there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization.
Abstract: background Angiotensin-converting–enzyme (ACE) inhibitors are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure. ACE inhibitors have also been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure. methods In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial, we tested the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy. The trial was a doubleblind, placebo-controlled study in which 8290 patients were randomly assigned to receive either trandolapril at a target dose of 4 mg per day (4158 patients) or matching placebo (4132 patients). results The mean (±SD) age of the patients was 64±8 years, the mean blood pressure 133±17/78±10 mm Hg, and the mean left ventricular ejection fraction 58±9 percent. The patients received intensive treatment, with 72 percent having previously undergone coronary revascularization and 70 percent receiving lipid-lowering drugs. The incidence of the primary end point — death from cardiovascular causes, myocardial infarction, or coronary revascularization — was 21.9 percent in the trandolapril group, as compared with 22.5 percent in the placebo group (hazard ratio in the trandolapril group, 0.96; 95 percent confidence interval, 0.88 to 1.06; P = 0.43) over a median follow-up period of 4.8 years. conclusions In patients with stable coronary heart disease and preserved left ventricular function who are receiving “current standard” therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization.
1,079 citations
TL;DR: Pravastatin reduces cardiovascular event rates in people with or at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range, and the absolute benefit that resulted from use of pravastsatin was greater than in those with normal renal function.
Abstract: Background— Limited data describe the cardiovascular benefit of HMG-CoA reductase inhibitors (statins) in people with moderate chronic kidney disease (CKD). The objective of this analysis was to determine whether pravastatin reduced the incidence of cardiovascular events in people with or at high risk for coronary disease and with concomitant moderate CKD. Methods and Results— We analyzed data from the Pravastatin Pooling Project (PPP), a subject-level database combining results from 3 randomized trials of pravastatin (40 mg daily) versus placebo. Of 19 700 subjects, 4491 (22.8%) had moderate CKD, defined by an estimated glomerular filtration rate of 30 to 59.99 mL/min per 1.73 m2 body surface area. The primary outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Moderate CKD was independently associated with an increased risk of the primary outcome (adjusted HR 1.26, 95% CI 1.07 to 1.49) compared with those with normal renal function. Among the 4...
379 citations
TL;DR: Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF ≤40% when added to standard therapies including ACE inhibitors, β-blockers, and an aldosterone antagonist.
Abstract: observed for 2 to 4 years (median, 40 months). The primary outcome (time to first event by intention to treat) was cardiovascular death or CHF hospitalization for each trial, with all-cause mortality a secondary end point in the pooled analysis of the low LVEF trials. Of the patients in the candesartan group, 817 (35.7%) experienced cardiovascular death or a CHF hospitalization as compared with 944 (41.3%) in the placebo group (HR 0.82; 95% CI 0.74 to 0.90; P0.001) with reduced risk for both cardiovascular deaths (521 [22.8%] versus 599 [26.2%]; HR 0.84 [95% CI 0.75 to 0.95]; P0.005) and CHF hospitalizations (516 [22.5%] versus 642 [28.1%]; HR 0.76 [95% CI 0.68 to 0.85]; P0.001). It is important to note that all-cause mortality also was significantly reduced by candesartan (642 [28.0%] versus 708 [31.0%]; HR 0.88 [95% CI 0.79 to 0.98]; P0.018). No significant heterogeneity for the beneficial effects of candesartan was found across prespecified and subsequently identified subgroups including treatment with ACE inhibitors, -blockers, an aldosterone antagonist, or their combinations. The study drug was discontinued because of adverse effects by 23.1% of patients in the candesartan group and 18.8% in the placebo group; the reasons included increased creatinine (7.1% versus 3.5%), hypotension (4.2% versus 2.1%), and hyperkalemia (2.8% versus 0.5%), respectively (all P0.001). Conclusion—Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF 40% when added to standard therapies including ACE inhibitors, -blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted. (Circulation. 2004;110:2618-2626.)
359 citations
265 citations
TL;DR: Candesartan reduced sudden death and death from worsening heart failure in patients with symptomatic heart failure, although this reduction was most apparent in patientsWith systolic dysfunction.
Abstract: Background— Patients with heart failure are at increased risk of sudden death and death attributed to progressive pump failure. We assessed the effect of candesartan on cause-specific mortality in patients enrolled in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Methods and Results— The CHARM program consisted of 3 component trials that enrolled patients with symptomatic heart failure: CHARM-Alternative (n=2028; LVEF⩽40% and ACE intolerant), CHARM-Added (n=2548; LVEF⩽40%, already on ACE inhibitors), and CHARM-Preserved (n=3023; LVEF >40%). Patients were randomized to candesartan, titrated to 32 mg QD, or placebo and were followed up for a median of 37.7 months. All deaths were reviewed by a blinded adjudication committee and categorized according to prespecified definitions on the basis of a narrative and source documentation. The number and rate of deaths by cause were calculated for each of the component trials and the overall program. Of all the p...
236 citations
TL;DR: In patients receiving tirofiban and aspirin, enoxaparin is a suitable alternative to unfractionated heparin for treatment of non-ST-elevation ACS and is consistent with prior trials performed without the use of glycoprotein IIb/IIIa inhibitors.
Abstract: ContextEnoxaparin or the combination of glycoprotein IIb/IIIa inhibitor tirofiban
with unfractionated heparin independently have shown superior efficacy over
unfractionated heparin alone in patients with non–ST-elevation acute
coronary syndromes (ACS) It is not clear if combining enoxaparin with glycoprotein
IIb/IIIa inhibitors is as safe or as effective as the current standard combination
of unfractionated heparin with glycoprotein IIb/IIIa inhibitorsObjectiveTo assess efficacy and safety of the combination of enoxaparin and tirofiban
compared with unfractionated heparin and tirofiban in patients with non–ST-elevation
ACSDesign, Setting, and ParticipantsA prospective, international, open-label, randomized, noninferiority
trial of 1 mg/kg of enoxaparin every 12 hours (n = 2026) compared with weight-adjusted
intravenous unfractionated heparin (n = 1961) in patients with non–ST-elevation
ACS receiving tirofiban and aspirin Phase A of the A to Z trial was conducted
between December 1999 and May 2002Main Outcome MeasuresDeath, recurrent myocardial infarction, or refractory ischemia at 7
days in the intent-to-treat population with boundaries set for superiority
and noninferiority Safety based on measures of bleeding using the Thrombolysis
in Myocardial Infarction (TIMI) classification systemResultsA total of 169 (84%) of 2018 patients randomized to enoxaparin experienced
death, myocardial infarction, or refractory ischemia at 7 days compared with
184 (94%) of 1952 patients randomized to unfractionated heparin (hazard ratio
[HR], 088; 95% confidence interval [CI], 071-108) This met the prespecified
criterion for noninferiority All components of the composite primary and
secondary end points favored enoxaparin except death, which occurred in only
1% of patients (23 for enoxaparin and 17 for unfractionated heparin) Rates
for any TIMI grade bleeding were low (30% for enoxaparin and 22% for unfractionated
heparin; P = 13) Using a worst-case approach that
combined 2 independent bleeding evaluations, use of enoxaparin was associated
with 1 additional TIMI major bleeding episode for each 200 patients treatedConclusionsIn patients receiving tirofiban and aspirin, enoxaparin is a suitable
alternative to unfractionated heparin for treatment of non–ST-elevation
ACS The 12% relative and 1% absolute reductions in the primary end point
in favor of enoxaparin met criterion for noninferiority and are consistent
with prior trials performed without the use of glycoprotein IIb/IIIa inhibitors
231 citations
TL;DR: The poor prognosis of patients with newly diagnosed diabetes, despite having baseline characteristics similar to those of patients without diabetes, supports the idea that metabolic abnormalities contribute to their adverse outcomes.
Abstract: Background— A prior diagnosis of diabetes mellitus is associated with adverse outcomes after acute myocardial infarction (MI), but the risk associated with a new diagnosis of diabetes in this setting has not been well defined. Methods and Results— We assessed the risk of death and major cardiovascular events associated with previously known and newly diagnosed diabetes by studying 14 703 patients with acute MI enrolled in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Patients were grouped by diabetic status: previously known diabetes (insulin use or diagnosis of diabetes before MI, n=3400, 23%); newly diagnosed diabetes (use of diabetic therapy or diabetes diagnosed at randomization [median 4.9 d after infarction], but no known diabetes at presentation, n=580, 4%); or no diabetes (n=10 719). Patients with newly diagnosed diabetes were younger and had fewer comorbid conditions than did patients with previously known diabetes. At 1 year after enrollment, patients with previously known and ne...
216 citations
TL;DR: HF and/or LVSD is common in the general contemporary MI population and precedes 80.3% of all in-hospital deaths after MI, and survivors of early MI-associated HF and or LVSD have more complications, longer hospitalisations, and are more likely to die during hospitalisation.
Abstract: Aims We analysed the contemporary incidence, outcomes, and predictors of heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) before discharge in patients with acute myocardial infarction (MI). The baseline presence of HF or LVSD, or its development during hospitalisation, increases short- and long-term risk after MI, yet its incidence, predictors, and outcomes have not been well described in a large, international, general. MI population. Methods and results The VALIANT registry included 5573 consecutive MI patients at 84 hospitals in nine countries from 1999 to 2001. A multivariable logistic survival model was constructed using baseline variables to determine the adjusted mortality risk for those with in-hospital HF and/or LVSD. Baseline variables were also tested for associations with in-hospital HF and/or LVSD. Of the 5566 patients analysed, 42% had HF and/or LVSD during hospitalisation. Their in-hospital. mortality rate was 13.0% compared with 2.3% for those without HF and/or without LVSD. After adjustment for other baseline risk factors, in-hospital HF and/or LVSD carried a hazard ratio for inhospital mortality of 4.12 (95% confidence interval: 3.08-5.56). Patients with HF and/or LVSD also had disproportionately higher rates of other cardiovascular events. Conclusions HF and/or LVSD is common in the general contemporary MI population and precedes 80.3% of all in-hospital deaths after MI. Survivors of early MI-associated HF and/or LVSD have more complications, Longer hospitalisations, and are more likely to die during hospitalisation. Although baseline variables can identify MI patients at highest risk for HF and/or LVSD, such patients are less likely to receive indicated procedures and medical therapies. (C) 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
TL;DR: Among patients who have recently had an acute coronary syndrome, an intensive lipidlowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen.
Abstract: background Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. methods We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24). results The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan–Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen. conclusions Among patients who have recently had an acute coronary syndrome, an intensive lipidlowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.
TL;DR: CKD was associated with a heightened risk for all major CV events after MI, particularly among subjects with an estimated glomerular filtration rate <45 mL · min−1 · 1.73 m−2, and Randomization to captopril resulted in a reduction of CV events irrespective of baseline kidney function.
Abstract: Background— Persons with end-stage renal disease and those with lesser degrees of chronic kidney disease (CKD) have an increased risk of death after myocardial infarction (MI) that is not fully explained by associated comorbidities. Future cardiovascular event rates and the relative response to therapy in persons with mild to moderate CKD are not well characterized. Methods and Results— We calculated the estimated glomerular filtration rate (eGFR) using the 4-variable Modification of Diet in Renal Disease method in 2183 Survival And Ventricular Enlargement (SAVE) trial subjects. SAVE randomized post-MI subjects (3 to 16 days after MI) with left ventricular ejection fraction ≤40% and serum creatinine <2.5 mg/dL to captopril or placebo. Cox proportional hazards models were used to evaluate the relative hazard rates for death and cardiovascular events associated with reduced eGFR. Subjects with reduced eGFR were older and had more extensive comorbidities. The multivariable adjusted risk ratio for total morta...
TL;DR: In patients who survived myocardial infarction with left ventricular dysfunction, diabetes increased risk of death from all causes even after controlling for differences in other risk factors.
Abstract: Background Diabetes is a major risk factor for developing coronary heart disease. In patients with diabetes who survived myocardial infarction (MI), less is known about subsequent morbidity and mortality. We evaluated the effects of diabetes in post-MI patients with left ventricular dysfunction on cardiovascular events and death. Methods The Survival and Ventricular Enlargement, a randomized, double-blind, placebo-controlled multicenter trial, evaluated the efficacy of captopril vs placebo in 2231 patients following acute MI with left ventricular dysfunction defined as an ejection fraction less than or equal to 40%. Patients were randomly assigned to captopril or placebo 3 to 16 days following MI and were followed up for 2 to 5 years (mean, 3.5 years). Results Among the 2231, 496 (22.2%) were patients with a history of diabetes, of which 168 (33.9%) were treated with insulin. Patients with diabetes were significantly older; more likely to be women; have a history of prior MI or hypertension; be obese or manifest Killip class II or greater; and have higher systolic blood pressure, pulse pressure, and heart rate, as well as lower ejection fraction. During follow-up, 31.3% of patients with diabetes and 20.1% of nondiabetic patients died (P Conclusions In patients who survived MI with left ventricular dysfunction, diabetes increased risk of death from all causes even after controlling for differences in other risk factors. Patients with diabetes treated with insulin have a particularly higher mortality risk. Patients with diabetes who survived MI with left ventricular dysfunction, in particular those receiving insulin, are at high risk of subsequent mortality and cardiovascular events and thus require intensive risk factor modification, as well as evaluation for novel therapies.
TL;DR: Among individuals with hypertension and diabetic nephropathy, both the degree of albuminuria and lower serum albumin levels provide additional prognostic information concerning cardiovascular risk, in addition to traditional coronary risk factors.
TL;DR: The investigators concluded that the A to Z trial did not achieve the prespecified end point of benefit with early high-dose simvastatin therapy, but it demonstrated that aggressive LDL cholesterol lowering following ACS prevents death and major cardiovascular events.
Abstract: Study Question: Phase Z of the A to Z trial was designed to evaluate a strategy of early initiation of intensive treatment with simvastatin (80 mg) in ACS patients compared with a delayed, less intensive strategy. Methods: The study was a randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n=2265) compared with placebo for 4 months followed by 20 mg/d of simvastatin (n=2232). The primary end point was a composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke. Follow-up was at least 6 months and up to 24 months. Results: Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin-only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin-only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95% confidence interval [CI] 0.76–1.04; p=0.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) patients in the two groups (HR, 0.75; 95% CI, 0.57–1.00; p =0.05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95% CI, 0.83–1.25; p =0.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin-only group (HR, 0.75; 95% CI, 0.60–0.95; p =0.02). Myopathy (creatine kinase >10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo ( p =0.02). Conclusions: The investigators concluded that the trial did not achieve the prespecified end point of benefit with early high-dose simvastatin therapy. Perspective: Early initiation of an intensive simvastatin regimen when compared with the delayed initiation of a less intensive simvastatin regimen did not show significant clinical benefit. The findings from the MIRACL and PROVE-IT studies, however, demonstrated that aggressive LDL cholesterol lowering following ACS prevents death and major cardiovascular events. The unfavorable risk-benefit relationship observed in the A to Z trial should not diminish the value of intensive statin treatment in secondary prevention, including ACS patients. For now, though, the 80-mg/d dose of simvastatin should be used with caution, particularly because other effective agents are available. DM
TL;DR: In patients with LV dysfunction after an MI, light-to-moderate alcohol intake either at baseline or following MI did not alter the risk for the development of HF requiring hospitalization or an open-label angiotensin-converting enzyme inhibitor.
TL;DR: Ischemic symptoms occurring before MI may protect against LV remodeling and the protective effect of pre-infarction angina appeared to be attenuated in diabetic patients.
TL;DR: The evaluation of the effects of ARBs in CHF and AMI has been challenging because of the incontrovertible role of ACE inhibitors, raising questions about trial design, dose selection, statistics, and even ethics.
Abstract: The value of angiotensin-converting enzyme (ACE) inhibitors in reducing mortality rates and major nonfatal cardiovascular events in patients with chronic heart failure (CHF) caused by left ventricular systolic dysfunction (LVSD) and in those with acute myocardial infarction (AMI) has been established by multiple randomized clinical trials.1–3 Angiotensin II type 1 receptor blockers (ARBs) offer an alternative means of blocking the renin-angiotensin system (RAS).4,5 The hypothetical reasons why an ARB might be more effective or better tolerated (or both) than an ACE inhibitor have been reviewed in detail.6,7 Briefly, angiotensin II is produced by enzymes other than ACE, meaning that ACE inhibitors might be less effective at blocking this peptide than an ARB (Figure 1).8,9 Angiotensin type 1 (AT1) receptor blockade also makes more angiotensin II available to stimulate the unblocked AT2 receptor (and perhaps other AT receptor subtypes)10,11 with purported beneficial actions in reducing cardiovascular disease progression.12
Figure 1. Schematic of RAS and site of action of ACE inhibitors and ARBs.
Unlike ARBs, ACE (kininase II) inhibitors inhibit bradykinin breakdown. Augmentation of bradykinin may have actions including potentiation of vasodilation, fibrinolytic effects, and inhibition of cellular growth and division, which may contribute to the benefits of ACE inhibitors.6,13,14 Conversely, bradykinin accumulation may cause some of the adverse effects of ACE inhibitors, ie, cough, rash, and angioedema.6,7
The evaluation of the effects of ARBs in CHF and AMI has therefore been challenging because of the incontrovertible role of ACE inhibitors in these conditions, raising questions about trial design, dose selection, statistics, and even ethics.15,16 A particular issue has been the need for direct comparisons, including formally conducted tests for “noninferiority,” with the implications this has for patient selection, choice of ACE inhibitor and dose, sample size, and end points. …
TL;DR: In patients with hypertensive heart disease, the components of therapy must comprise optimization of BP and regression of LVH, and future targets of therapy may include regression of myocardial fibrosis, normalization of LA size, and improvement in LV diastolic function.
Journal Article•
TL;DR: In this paper, the authors measured the QRS duration in 403 patients with acute myocardial infarction (MI) complicated by left ventricular dysfunction, signs or symptoms of heart failure, or both, who were enrolled in the Valsartan in Acute Myocardial Infarction echo study.
Abstract: BACKGROUND
Prolongation of the QRS duration has been shown to be associated with adverse outcomes among heart failure (HF) patients. The association of QRS duration with clinical outcomes in the post-myocardial infarction (MI) setting is less well defined.
OBJECTIVES
To assess the prognostic significance of QRS duration prolongation on initial electrocardiogram after acute MI.
METHODS
QRS duration was measured in 403 patients with MI complicated by left ventricular dysfunction, signs or symptoms of HF, or both, who were enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) echo study. The cohort was divided into quartiles of QRS duration (<75 ms, 75-88 ms, 89-108 ms, >108 ms). The number of clinical events were determined and compared across the groups.
RESULTS
Increasing QRS duration is associated with a higher incidence of HF, sudden death (SD), and cardiovascular (CV) death (P-trend <0.05) but not with stroke or recurrent MI. The univariate relative risks for HF, SD, and CV death with increasing QRS duration quartiles were 1.31 (95% CI, 1.06-1.64), 1.57 (95% CI, 1.03-2.40), and 1.31 (95% CI, 1.03-1.66), respectively, but QRS duration did not remain independently predictive of adverse outcome after adjusting for the 10 most predictive baseline covariates. Baseline end-diastolic and end-systolic volumes were larger and ejection fraction was lower in the higher QRS quartile groups.
CONCLUSIONS
Prolonged QRS duration, even within the normal range, is associated with larger ventricular volumes, reduced systolic function, and an increased risk for development of HF, SD, and CV death after MI but appears to be a marker, rather than an independent predictor, for increased risk.
TL;DR: When a conservative approach to catheterisation and PCI was planned for ACS patients receiving tirofiban and aspirin, enoxaparin was associated with superior efficacy and similar bleeding vs UFH.
Abstract: Aims In high risk patients with non-ST elevation acute coronary syndromes (ACS), enoxaparin is generally preferred to unfractionated heparin (UFH). However, less is known about the relative merits of these two forms of heparin in patients receiving concomitant glycoprotein IIb/IIIa inhibitors.
Methods and results The A phase of the A-to-Z trial was an open label non-inferiority trial in which 3987 patients with non-ST elevation ACS were randomised to receive either enoxaparin or UFH in combination with aspirin and tirofiban. Inclusion required either ST depression or cardiac biomarker elevation. While the selection of an early management strategy (invasive or conservative) was at the discretion of the local investigator, investigators were asked to designate their plans for an invasive or conservative strategy on the case record form. An early conservative strategy was specified for 1778 patients (45%); this subgroup forms the population for the present analyses. Among patients with a planned conservative strategy, baseline characteristics were similar between those randomised to UFH ( n =872) and those randomised to enoxaparin ( n =906). The primary endpoint of death, new MI, or documented refractory ischaemia within 7 days of randomisation occurred in 10.6% of patients randomised to UFH and 7.7% of patients randomised to enoxaparin (HR 0.72; 95% CI 0.53–0.99; p =0.04). The combined rate of TIMI major, minor, or loss no-site bleeding was 1.3% in patients treated with UFH and 1.8% in those treated with enoxaparin ( p = ns ).
Conclusions When a conservative approach to catheterisation and PCI was planned for ACS patients receiving tirofiban and aspirin, enoxaparin was associated with superior efficacy and similar bleeding vs UFH.
TL;DR: C candesartan improves NYHA functional class to a similar extent to other proven treatments for CHF when added to these other treatments when addition to the CHARM component trials.
Abstract: Aims To evaluate the effect of the angiotensin receptor blocker candesartan on New York Heart Association (NYHA) functional class in a broad spectrum of patients with chronic heart failure (CHF).
Methods and results Patients in the CHARM Programme with symptomatic CHF were randomized to placebo ( n =3796) or candesartan ( n =3803) and followed for a median of 38 months. NYHA class was assessed at baseline, at two weekly intervals during dose titration and 4 monthly thereafter. Patients were classified as "better", "unchanged" or "worse" at the end of the study compared to baseline. Both a simple "last visit carried forward" (LVCF) analysis and "worst rank carried forward" (WRCF) analysis (where patients who died were allocated NYHA class V) were used. In the LVCF analysis, compared to placebo, more candesartan patients improved (35.4% versus 32.5%) and fewer worsened (9.0% versus 10.3%) in NYHA class ( p =0.003). The WRCF analysis also showed a better overall change in NYHA class with candesartan compared to placebo. There was no heterogeneity in the response to candesartan between the CHARM component trials.
Conclusions Candesartan improves NYHA functional class to a similar extent to other proven treatments for CHF when added to these other treatments.
TL;DR: It is concluded that antecedent hypertension is associated with subsequent LV dilation in patients after acute myocardial infarction with LV systolic dysfunction and was not modified by diabetes mellitus, myocardia infarct segment length, or captopril use.
Abstract: Whether antecedent systemic hypertension influences the risk of subsequent left ventricular (LV) dilation in patients after an acute myocardial infarction with LV systolic dysfunction is unclear. We assessed echocardiographic evidence of ventricular remodeling from baseline (mean +/- SD 11 +/- 3 days) to 2 years after an acute myocardial infarction in 122 hypertensive (defined as a history of treated hypertension, baseline systolic blood pressure > or =140 or baseline diastolic blood pressure > or =90 mm Hg) and 334 nonhypertensive patients in the Survival and Ventricular Enlargement echocardiographic substudy. Compared with nonhypertensives, baseline heart size, defined as the sum of the average short- and long-axis LV cavity areas, was similar (70.1 +/- 11.9 vs 68.8 +/- 11.2 cm(2), p = 0.33 at end-diastole; 50.1 +/- 11.3 vs 48.8 +/- 10.8 cm(2), p = 0.31 at end-systole), but short-axis LV myocardial area (24.7 +/- 4.3 vs 25.7 +/- 5.0 cm(2), p = 0.043) and wall thickness (1.15 +/- 0.16 vs 1.21 +/- 0.17 cm, p = 0.004) at end-diastole were greater among hypertensives. The myocardial infarct segment lengths were similar in the 2 groups (p = 0.22). Although LV cavity areas increased significantly in the 2 groups from baseline to 2 years (p 0.30). After adjusting for known confounders, antecedent hypertension was associated with a doubling of the risk of LV dilation (50.8% vs 37.7%, odds ratio 2.09, 95% confidence interval 1.27 to 3.45, p = 0.004). This association was not modified by diabetes mellitus, myocardial infarct segment length, or captopril use (all p values for interaction >0.10). We conclude that antecedent hypertension is associated with subsequent LV dilation in patients after acute myocardial infarction with LV systolic dysfunction.
TL;DR: The understanding of the interrelation between AHF and acute coronary syndrome (ACS) is expanded, the impact for patients across the spectrum of ACS presentations is clarified, and disturbing revelations on signaling pathways and genetic expression are provided.
Abstract: Patients manifesting symptomatic pulmonary congestion during an acute myocardial infarction have long been recognized to be at heightened risk of both short- and long-term mortality.1–3 Acute heart failure (AHF) complicates acute myocardial infarction as a result of a complex interaction of structural, hemodynamic, neurohormonal, and genetic maladaptations. Abrupt myocyte loss leading to contractile dysfunction and AHF is an obvious mechanism, and the extent of biomarker elevation correlates with prognosis and the range of functional recovery.4 In those without extensive myocyte necrosis, postischemic left ventricular systolic dysfunction (LVSD) leading to AHF can result from transient myocardial stunning or hibernation depending on the extent of coronary reperfusion.5 Ventricular remodeling can increase wall stress to viable regions that may be relatively underperfused, furthering ischemia and adding to this cycle. Ischemia-induced impairment in myocardial relaxation can increase left ventricular filling pressures irrespective of global systolic function and lead to AHF. Furthermore, ischemia can also precipitate acute mitral regurgitation in some patients, contributing to the risk of pulmonary congestion. Recent data also suggest that AHF potentiates apoptosis in and outside the infarct zone,6 which focuses attention beyond mechanics, hemodynamics, and perfusion to alterations in signaling pathways and genetic expression. Regardless of which processes dominate in individual patients, it is clear that the intersection of AHF and myocardial infarction remains deadly even in the current era of acute reperfusion.7
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In this issue of Circulation , the Global Registry of Acute Coronary Events (GRACE) investigators8 expand on our understanding of the interrelation between AHF and acute coronary syndrome (ACS), clarify the impact for patients across the spectrum of ACS presentations, and provide disturbing revelations on …
TL;DR: In their third version of U.S. federal guidelines, the National Cholesterol Education Program Adult Treatment Panel III elevated diabetes from a major risk factor to a coronary heart disease (CHD) risk equivalent, and recommended that patients with diabetes be treated just as aggressively as secondary prevention patients without diabetes.
Abstract: In their third version of U.S. federal guidelines, the National Cholesterol Education Program Adult Treatment Panel III elevated diabetes from a major risk factor to a coronary heart disease (CHD) risk equivalent (1, 2). The rationale for this change derives, in part, from earlier observations that patients with diabetes have several-fold increased risks of CHD (3), which are even greater in women than men (4). In fact, it has been suggested that at any given age, diabetes eliminates the lower absolute risk of CHD in women compared with men. Specifically, a middle-aged woman with diabetes has an absolute risk of CHD approximately equal to her male counterpart without diabetes. Furthermore, in a prospective cohort study, nondiabetic subjects with prior CHD had a 7-year event rate of ∼18.8%, whereas diabetic subjects without prior CHD had an event rate of ∼20% (5). Whether such high absolute risks apply to patients with newly diagnosed diabetes is less clear. Nonetheless, current U.S. federal guidelines recommend that patients with diabetes be treated just as aggressively as secondary prevention patients without diabetes (i.e., those who have already experienced a CHD event).
With respect to secondary prevention, aspirin conclusively reduces risks of subsequent myocardial infarction (MI) by about one-third, stroke by about one-fourth, and vascular death by about one-sixth (6, 7). In primary prevention, aspirin conclusively reduces the risk of a first MI by about one-third, but the numbers of strokes and vascular deaths in the five published primary prevention trials preclude firm conclusions. Nonetheless, based on meta-analyses of risks (8) and benefits (9), recent U.S. Preventive Services Task Force Guidelines recommend that aspirin also be considered for all apparently …
TL;DR: In survivors of an acute MI with LV systolic dysfunction, antecedent hypertension was associated with a greater risk of subsequent adverse cardiovascular events, not directly explained by elevated blood pressure levels.
TL;DR: There is evidence that the increased survival demonstrated in randomized clinical trial cohorts has been translated to the unselected general population, and treatment continues to be refined and improved.
TL;DR: During the Irbesartan Diabetic Nephropathy Trial, 1,387 participants with type 2 diabetes mellitus, hypertension, and nephropathy underwent serial electrocardiograms for the identification of Q-wave myocardial infarction, accounting for 14% of all first nonfatal MIs.
Abstract: During the Irbesartan Diabetic Nephropathy Trial, 1,387 participants with type 2 diabetes mellitus, hypertension, and nephropathy underwent serial electrocardiograms for the identification of Q-wave myocardial infarction (MI). During a mean follow-up of 2.5 years, 14 of 99 first nonfatal MIs in this group were clinically unrecognized, accounting for 14% of all first nonfatal MIs.