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This study compared moderate lipid lowering with pravastatin and intensive lipid lowering with atorvastatin in patients after an acute coronary syndrome. Over a mean follow-up period of two years, those treated with the intensive lipid-lowering regimen had better outcomes. The findings add to a growing body of evidence supporting the use of intensive lipid lowering. Several large, randomized, controlled trials have documented that cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduces the risk of death or cardiovascular events across a wide range of cholesterol levels whether or not patients have a history of coronary artery disease. 1 – 7 The doses of statins used in these trials reduced low-density lipoprotein (LDL) cholesterol levels by 25 to 35 percent, and current guidelines recommend a target LDL cholesterol level of less than 100 mg per deciliter (2.59 mmol per liter) for patients with established coronary artery disease or diabetes. 8 , 9 It is not clear whether lowering lipid . . .

OBJECTIVE:-- PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure. RESEARCH DESIGN AND METHODS-- PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression. RESULTS:-- More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025). CONCLUSIONS:-- Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure.

Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor γ (PPAR γ) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34·5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0·90, 95% CI 0·80–1·02, p=0·095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0·84, 0·72–0·98, p=0·027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

Background Antiplatelet therapy is essential treatment for acute coronary syndromes (ACS). Current therapies, however, have important limitations affecting their clinical success. Ticagrelor, the first reversible oral P2Y12 receptor antagonist, provides faster, greater, and more consistent adenosine diphosphate–receptor inhibition than clopidogrel. The phase III PLATelet inhibition and patient Outcomes (PLATO) trial is designed to test the hypothesis that ticagrelor compared with clopidogrel will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS. Methods PLATO is an international, randomized, double-blind, event-driven trial involving >18,000 patients hospitalized for ST-elevation ACS with scheduled primary percutaneous coronary intervention or for non–ST-elevation ACS. After loading doses of ticagrelor 180 mg or clopidogrel 300 mg in a double-blind, double-dummy fashion (with provision for additional 300 mg clopidogrel at percutaneous coronary intervention), patients will receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 6 to 12 months on top of acetylsalicylic acid. The primary efficacy end point is time to first occurrence of death from vascular causes, myocardial infarction, or stroke. The primary safety variable is PLATO-defined major bleeding. An extensive substudy program will explore the pathophysiology of ACS, indicators of prognosis and response to treatment, mechanisms of effect and safety of the study medications, health economics, and quality of life. Conclusion The PLATO study will provide a pivotal comparison of the efficacy and safety of ticagrelor with those of clopidogrel in ACS patients, together with extensive information on treatment outcomes in different subsets of ACS in a broad patient population.

Studies have suggested that infection with Chlamydia pneumoniae may have a role in the pathogenesis of coronary artery disease. This study casts doubt on the idea, since two years of treatment with gatifloxacin, an antibiotic with bactericidal activity against C. pneumoniae, had no beneficial effect on clinical outcomes. This study complements the results of the study by Grayston et al. reported in this issue of the Journal, which led to a similar conclusion. This study casts doubt on the idea that infection with C. pneumoniae may have a role in the pathogenesis of coronary artery disease. Two years of treatment with gatifloxacin, an antibiotic with bactericidal activity against C. pneumoniae, had no beneficial effect on clinical outcomes. Although epidemiologic studies have identified numerous risk factors for atherosclerosis, many patients do not exhibit such risk factors, and this has prompted a search for additional contributors to the progression of the disease. 1 Infection with various pathogens has been implicated in the development of coronary artery disease. Specifically, Chlamydia pneumoniae has been associated with a doubling of the risk of atherosclerosis or myocardial infarction. 2 – 7 The organism has been detected in human atheroma, 5 , 6 and animal models have shown that new infection with C. pneumoniae results in more extensive atherosclerosis. 7 – 10 Although not all studies show a significant relationship between . . .

In a multicenter, randomized trial, ticagrelor — a reversible inhibitor of the adenosine diphosphate receptor P2Y12 — was compared with clopidogrel in patients who had an acute coronary syndrome with or without ST-segment elevation. At 12 months, the primary end point of death from vascular causes, myocardial infarction, or stroke occurred less often with ticagrelor. Ticagrelor was not associated with an increase in the risk of major bleeding. At 12 months, the primary end point of death from vascular causes, myocardial infarction, or stroke occurred less often with ticagrelor. Ticagrelor was not associated with an increase in the risk of major bleeding. In patients who have acute coronary syndromes with or without ST-segment elevation, current clinical practice guidelines 1 – 4 recommend dual antiplatelet treatment with aspirin and clopidogrel. The efficacy of clopidogrel is hampered by the slow and variable transformation of the prodrug to the active metabolite, modest and variable platelet inhibition, 5 , 6 an increased risk of bleeding, 7 , 8 and an increased risk of stent thrombosis and myocardial infarction in patients with a poor response. 9 As compared with clopidogrel, prasugrel, another thienopyridine prodrug, has a more consistent and pronounced inhibitory effect on platelets, 5 , 6 resulting in a lower risk of myocardial infarction and . . .

Antiplatelet therapy is essential treatment for acute coronary syndromes (ACS). Current therapies, however, have important limitations affecting their clinical success. Ticagrelor, the first reversible oral P2Y(12) receptor antagonist, provides faster, greater, and more consistent adenosine diphosphate-receptor inhibition than clopidogrel. The phase III PLATelet inhibition and patient Outcomes (PLATO) trial is designed to test the hypothesis that ticagrelor compared with clopidogrel will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS. PLATO is an international, randomized, double-blind, event-driven trial involving >18,000 patients hospitalized for ST-elevation ACS with scheduled primary percutaneous coronary intervention or for non-ST-elevation ACS. After loading doses of ticagrelor 180 mg or clopidogrel 300 mg in a double-blind, double-dummy fashion (with provision for additional 300 mg clopidogrel at percutaneous coronary intervention), patients will receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 6 to 12 months on top of acetylsalicylic acid. The primary efficacy end point is time to first occurrence of death from vascular causes, myocardial infarction, or stroke. The primary safety variable is PLATO-defined major bleeding. An extensive substudy program will explore the pathophysiology of ACS, indicators of prognosis and response to treatment, mechanisms of effect and safety of the study medications, health economics, and quality of life. The PLATO study will provide a pivotal comparison of the efficacy and safety of ticagrelor with those of clopidogrel in ACS patients, together with extensive information on treatment outcomes in different subsets of ACS in a broad patient population.

Charbonnel et al examine the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) that assesses the effect of pioglitazone, a peroxisome proliferator-activated receptor agonist, with anti-inflammatory and vascular properties, on the secondary prevention of macrovascular events in type 2 diabetes. Results show that the cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events. Furthermore, the characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes.

β blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II–IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0·35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. The mean study duration was 58 months (SD 6). The mean ejection fraction was 0·26 (0·07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0·83 [95% CI 0·74–0–93], p=0–0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0·94 [0·86–1–02], p=0·122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. Our results suggest that carvedilol extends survival compared with metoprolol.

Abstract Objective: To assess longitudinal trends in admissions, management, and inpatient mortality from acute myocardial infarction over 10 years. Design: Retrospective analysis based on the Nottingham heart attack register. Setting: Two district general hospitals serving a defined urban and rural population. Subjects: All patients admitted with a confirmed acute myocardial infarction during 1982-4 and 1989-92 (excluding 1991, when data were not collected). Main outcome measures: Numbers of patients, background characteristics, time from onset of symptoms to admission, ward of admission, treatment, and inpatient mortality. Results: Admissions with acute myocardial infarction increased from 719 cases in 1982 to 960 in 1992. The mean age increased from 62.1 years to 66.6 years (P<0.001), the duration of stay fell from 8.7 days to 7.2 days (P<0.001), and the proportion of patients aged 75 years and over admitted to a coronary care unit increased significantly from 29.1% to 61.2%. A higher proportion of patients were admitted to hospital within 6 hours of onset of their symptoms in 1989-92 than in 1982-4, but 15% were still admitted after the time window for thrombolysis. Use of ß blockers increased threefold between 1982 and 1992, aspirin was used in over 70% of patients after 1989, and thrombolytic use increased 1.3-fold between 1989 and 1992. Age and sex adjusted odds ratios for inpatient mortality remained unchanged over the study period. Conclusions: Despite an increasing uptake of the “proved” treatments, inpatient mortality from myocardial infarction did not change between 1982 and 1992. Key messages During 1982-92 major changes in management of myocardial infarction in an unselected population have been guided by the results of randomised trials Adjusted odds ratios for deaths in hospital from acute myocardial infarction did not change over this period despite an overall fall in recorded deaths from ischaemic heart disease in Nottingham The use of existing treatments needs to be optimised and new management strategies need to be introduced if inpatient mortality from myocardial infarction is to be reduced