Showing papers by "Eugene Braunwald published in 2008"

Biomarkers in heart failure.

Abstract: Heart failure results not only from cardiac overload or injury but also from a complex interplay among genetic, neurohormonal, inflammatory, and biochemical changes acting on cardiac myocytes, the cardiac interstitium, or both. This review focuses on biomarkers for heart failure other than routinely determined laboratory values and discusses how these might be used in assessing and managing heart failure.

State of the art: using natriuretic peptide levels in clinical practice.

Abstract: Natriuretic peptide (NP) levels (B-type natriuretic peptide (BNP) and N-terminal proBNP) are now widely used in clinical practice and cardiovascular research throughout the world and have been incorporated into most national and international cardiovascular guidelines for heart failure. The role of NP levels in state-of-the-art clinical practice is evolving rapidly. This paper reviews and highlights ten key messages to clinicians: 1) NP levels are quantitative plasma biomarkers of heart failure (HF). 2) NP levels are accurate in the diagnosis of HF. 3) NP levels may help risk stratify emergency department (ED) patients with regard to the need for hospital admission or direct ED discharge. 4) NP levels help improve patient management and reduce total treatment costs in patients with acute dyspnoea. 5) NP levels at the time of admission are powerful predictors of outcome in predicting death and re-hospitalisation in HF patients. 6) NP levels at discharge aid in risk stratification of the HF patient. 7) NP-guided therapy may improve morbidity and/or mortality in chronic HF. 8) The combination of NP levels together with symptoms, signs and weight gain assists in the assessment of clinical decompensation in HF. 9) NP levels can accelerate accurate diagnosis of heart failure presenting in primary care. 10) NP levels may be helpful to screen for asymptomatic left ventricular dysfunction in high-risk patients.

Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38

Abstract: Background—Patients with diabetes mellitus (DM) are at high risk for recurrent cardiovascular events after acute coronary syndromes, in part because of increased platelet reactivity. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed an overall reduction in ischemic events with more intensive antiplatelet therapy with prasugrel than with clopidogrel but with more bleeding. We compared prasugrel with clopidogrel among subjects with DM in TRITON-TIMI 38. Methods and Results—We classified 13 608 subjects on the basis of preexisting history of DM and further according to insulin use. Prespecified analyses of the primary (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and key secondary end points, including net clinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding) were compared by use of the log-rank test. We found that 3146 subjects had a preexisting history of DM, including 776 receiving insulin. The primary end point was reduced significantly with prasugrel among subjects without DM (9.2% versus 10.6%; hazard ratio [HR], 0.86; P0.02) and with DM (12.2% versus 17.0%; HR, 0.70; P0.001, Pinteraction0.09). A benefit for prasugrel was observed among DM subjects on insulin (14.3% versus 22.2%; HR, 0.63; P0.009) and those not on insulin (11.5% versus 15.3%; HR, 0.74; P0.009). Myocardial infarction was reduced with prasugrel by 18% among subjects without DM (7.2% versus 8.7%; HR, 0.82; P0.006) and by 40% among subjects with DM (8.2% versus 13.2%; HR, 0.60; P0.001, Pinteraction0.02). Although TIMI major hemorrhage was increased among subjects without DM on prasugrel (1.6% versus 2.4%; HR, 1.43; P0.02), the rates were similar among subjects with DM for clopidogrel and prasugrel (2.6% versus 2.5%; HR, 1.06; P0.81, Pinteraction0.29). Net clinical benefit with prasugrel was greater for subjects with DM (14.6% versus 19.2%; HR, 0.74; P0.001) than for subjects without DM (11.5% versus 12.3%; HR, 0.92; P0.16, Pinteraction0.05). Conclusions—Subjects with DM tended to have a greater reduction in ischemic events without an observed increase in TIMI major bleeding and therefore a greater net treatment benefit with prasugrel compared with clopidogrel. These data demonstrate that the more intensive oral antiplatelet therapy provided with prasugrel is of particular benefit to patients with DM. (Circulation. 2008;118:1626-1636.)

Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis.

Abstract: Context Although an invasive strategy is frequently used in patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS), data from some trials suggest that this strategy may not benefit women. Objective To conduct a meta-analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. Data Sources Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases (1970-April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non-ST-elevation myocardial infarction, and unstable angina. Study Selection Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. Data Extraction The principal investigators for each trial provided the sex-specific incidences of death, myocardial infarction (MI), and rehospitalization with ACS through 12 months of follow-up. Data Synthesis Data were combined across 8 trials (3075 women and 7075 men). The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65-1.01; 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55-0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction = .26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67; 95% CI, 0.50-0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77; 95% CI, 0.47-1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94; 95% CI, 0.61-1.44; P for interaction = .36) and was associated with a nonsignificant 35% higher odds of death or MI (OR, 1.35; 95% CI, 0.78-2.35; P for interaction = .08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46-0.67) if biomarker-positive and 0.72 (95% CI, 0.51-1.01) if biomarker-negative (P for interaction = .09). Conclusions In NSTE ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end point of death, MI, or rehospitalization with ACS. In contrast, our data provide evidence supporting the new guideline recommendation for a conservative strategy in low-risk women.

Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35

Abstract: Aims To determine whether an ultrasensitive assay can permit quantification of changes in circulating cardiac troponin (Tn) in the setting of stress test-induced myocardial ischaemia. Methods and results Blood samples were obtained before, immediately after, and 2 and 4 h after stress testing with nuclear perfusion imaging in 120 patients. Troponin was measured using commercial assays as well as with a novel, ultrasensitive cardiac TnI assay with a limit of detection of 0.2 pg/mL. Using the ultrasensitive assay, TnI was detectable in all patients before stress testing (median 4.4 pg/mL, interquartile range 3.1–8.6 pg/mL). By 4 h, troponin levels were unchanged in patients without ischaemia, whereas circulating levels had increased by a median of 1.4 pg/mL (24% increase) in patients with mild ischaemia ( P = 0.002) and by 2.1 pg/mL (40% increase) in patients with moderate-to-severe ischaemia ( P = 0.0006). In contrast, changes in troponin levels across patients in different ischaemic categories were indistinguishable using commercial troponin assays. When added to clinical factors, a >1.3 pg/mL increase in TnI using the ultrasensitive assay was an independent predictor of ischaemia (odds ratio 3.54, P = 0.007). Conclusion Transient stress test-induced myocardial ischaemia is associated with a quantifiable increase in circulating troponin that is detectable with a novel, ultrasensitive TnI assay.

Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial

Abstract: Aims In the TRITON-TIMI 38 trial, greater platelet inhibition with prasugrel reduced the first occurrence of the primary endpoint (cardiovascular death, MI, or stroke) compared with clopidogrel in patients with an acute coronary syndrome (ACS) undergoing planned percutaneous coronary intervention. We hypothesized that prasugrel would reduce not only first events but also recurrent primary endpoint events and therefore total events compared with clopidogrel. Methods and results Poisson regression analysis was performed to compare the number of occurrences of the primary endpoint between prasugrel and clopidogrel in TRITON-TIMI 38. Landmark analytic methods were used to evaluate the risk of a recurrent primary endpoint event following an initial non-fatal endpoint event. Among patients with an initial non-fatal event, second events were significantly reduced with prasugrel compared to clopidogrel (10.8 vs. 15.4%, HR 0.65, 95% CI 0.46–0.92; P = 0.016), as was CV death following the non-fatal event (3.7 vs. 7.1%, HR 0.46, 95% CI 0.25–0.82; P = 0.008). Overall there was a reduction of 195 total primary efficacy events with prasugrel vs. clopidogrel (rate ratio 0.79, 95% CI 0.71–0.87; P < 0.001). Recurrent bleeding events occurred infrequently (TIMI major non-CABG bleeds: four with prasugrel and two with clopidogrel). Study drug discontinuation was frequent following the initial major bleeding event (42% of patients discontinued study drug). Conclusion While standard statistical analytic techniques for clinical trials censor patients who experience a component of the primary composite endpoint, total cardiovascular events remain important to both patients and clinicians. Prasugrel, a more potent anti-platelet agent, reduced both first and subsequent cardiovascular events compared with clopidogrel in patients with ACS.

Effects of Ranolazine on Disease-Specific Health Status and Quality of Life Among Patients With Acute Coronary Syndromes Results from the MERLIN-TIMI 36 Randomized Trial

Abstract: Background— Ranolazine has been shown to reduce myocardial ischemia and symptom severity among selected patients with chronic angina. However, data regarding the effect of ranolazine on health status/quality of life (QOL) are limited. Methods and Results— We performed a prospective QOL analysis alongside the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-elevation acute coronary syndromes (MERLIN)-TIMI 36 trial, a randomized, double-blind, placebo-controlled trial of ranolazine in 6560 patients with non–ST-elevation acute coronary syndromes. Health status/QOL was evaluated at baseline and 4, 8, and 12 months after index hospitalization using the Seattle Angina Questionnaire, Rose dyspnea scale, SF-12, and EuroQol-5D. Health status/QOL scores improved significantly at all follow-up time points for both treatment arms. In the overall population, randomization to ranolazine was associated with minimal 12-month improvements in angina frequency and Seattle Angina Questionnaire-QOL (P<0.05). I...

Association Between ADAMTS1 Matrix Metalloproteinase Gene Variation, Coronary Heart Disease, and Benefit of Statin Therapy

Abstract: Objective— The purpose of this study was to investigate the association between the Ala227Pro polymorphism in the ADAMTS1 metalloproteinase gene and coronary heart disease and benefit from statin t...

ESC Forum on Drug Eluting Stents European Heart House, Nice, 27-28 September 2007.

Abstract: Drug-eluting stents (DES) were introduced into clinical practice in 2002 in order to reduce restenosis that occurred in 15–25% of patients receiving bare-metal stents (BMS).1–3 Subsequent trials with different types of DES confirmed their efficacy in this regard.4 However, late stent thrombosis was reported as early as 2004, typically in patients discontinuing dual anti-platelet therapy.5 At the European and World Congress of Cardiology in Barcelona 2006, alarming data were presented on a worse long-term prognosis following DES implantation compared with BMS.6,7 As a result both randomized controlled trials and registry data were scrutinized to validate these concerns, bearing in mind the differential values of both types of studies.8,9 Furthermore, the worldwide discussion on the long-term safety and efficacy of DES triggered the European Society of Cardiology together with the European Association for Percutaneous Cardiovascular Interventions to organize a forum on DES. On 27 and 28 September 2007, key opinion leaders in (interventional) cardiology and representatives from industry and regulatory bodies gathered in the European Heart House with the intention to review: (i) the most recent data on the long-term efficacy (reduction of restenosis, re-intervention) and safety (late stent thrombosis, myocardial infarction, mortality) of DES and its effects on outcome (survival, event-free survival), (ii) specific indications for DES; (iii) health economical analyses currently performed with DES; (iv) the DES registration process in Europe; (v) current and possible future trial designs. The overall goal was to provide general recommendations to the medical community for the use, clinical development, and future assessment of DES. In several randomized controlled trials comparing sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES) and BMS, increased rates of death or myocardial infarction were observed at follow-up, beyond the first year,6–8,10 while no excess …

Outcomes of Patients With Acute Coronary Syndrome and Previous Coronary Artery Bypass Grafting (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE IT-TIMI 22] and the Aggrastat to Zocor [A to Z] Trials)

Abstract: We examined the effects of intensive statin therapy in patients with acute coronary syndromes (ACSs) and previous coronary artery bypass graft surgery (CABG) participating in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) and the Aggrastat to Zocor (A to Z) trials. Of the 8,655 patients enrolled in PROVE IT-TIMI 22 or A to Z, 640 (7.4%) had undergone CABG before enrollment. After a median follow-up of 2 years, compared with patients without previous CABG, those with previous CABG had a higher risk of cardiovascular death (6.2% vs 2.8%), myocardial infarction (14.2% vs 6.6%), and readmission for ACS (7.9% vs 4.4%, p <0.001 for all comparisons) but a lower rate of repeat coronary revascularization (22.7% vs 26.9%, p = 0.01). Compared with moderate statin therapy, intensive statin therapy appeared to decrease the composite of cardiovascular death, myocardial infarction, stoke, and readmission for an ACS (A to Z primary end point) to a similar extent in patients with (26.1% vs 21.6%, hazard ratio 0.84, p = 0.27) and without (13.9% vs 12.0%, hazard ratio 0.86, p = 0.016) previous CABG, although the decrease was not statistically significant in the previous CABG group, likely due to the small number of patients with previous CABG. In conclusion, compared with patients with ACS without previous CABG, those with previous CABG have a higher risk for adverse cardiac events and may derive similar benefit from intensive statin therapy.

The management of heart failure: the past, the present, and the future.

Abstract: It is an honor to contribute to this inaugural issue of Circulation: Heart Failure and to provide some personal reflections on the management of heart failure (HF). I will comment on the past and the present and will venture to make some predictions about the future of this important subject. In 1950, as a medical student, I first learned about the management of congestive HF from the first edition of Harrison’s Principles of Internal Medicine ,1 which had just been published. Management consisted of strict bed rest, sedation, dietary sodium restriction, digitalis, venesection, and administration of morphine and mercurial diuretics; the latter were only modestly effective and were administered by painful intramuscular injection. All of these measures (other than mercurial diuretics) had not changed for about a half century. I replaced Harrison as the cardiology editor of Harrison’s Principles of Internal Medicine for the sixth edition,2 which was published in 1970. The management of HF, while still adhering to the principles set forth in the first edition, included 3 new aspects: (1) control of fluid retention with the (then) new orally effective diuretics—thiazides, the powerful new loop diuretics, as well as potassium-retaining diuretics (because of the widespread use of these agents, the adjective “congestive” was gradually eliminated from the name of the condition); (2) recognition and vigorous treatment of the precipitating causes of HF, such as infection, pulmonary embolism, and arrhythmias; and (3) intravenous dopamine, the powerful new β-adrenergic agonist for the management of acute, decompensated HF, including cardiogenic shock. If we move forward 35 years and 10 editions of Harrison’s Principles of Internal Medicine , we come to the 16th edition, in which my chapter called attention to the importance of attempting to prevent HF in patients who were at risk for this condition but without overt …

The Problem of Persistent Platelet Activation in Acute Coronary Syndromes and Following Percutaneous Coronary Intervention

Abstract: Platelets play a central role in the atherosclerotic inflammatory response, thrombotic vascular occlusion, microembolization, vasoconstriction, and plaque progression. Persistent platelet activation poses a serious problem among patients with acute coronary syndromes (ACS) and those who have undergone percutaneous coronary intervention (PCI), placing them at risk for ischemic events and subacute stent thrombosis. Patients undergoing PCI are at risk for further ischemic events because of procedure-related platelet activation as well as the inherent persistent platelet hyperreactivity and enhanced thrombin generation associated with ACS. Persistent platelet activation following an acute coronary event and/or PCI supports incorporating antiplatelet strategies into the standard medical management of such patients. In this clinical setting, antiplatelet therapies are capable of improving outcomes. Aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors, the 3 major pharmacologic approaches to persistent platelet activation, target various levels of the hemostatic pathways and thrombus formation.

Lack of association between soluble CD40L and risk in a large cohort of patients with acute coronary syndrome in OPUS TIMI-16.

Abstract: Background Previous studies have suggested that elevated soluble CD40 ligand (sCD40L) levels predict adverse cardiovascular outcomes in patients with acute coronary syndromes (ACS). Recently, questions have been raised regarding the influence of pre-analytical and analytical conditions on measurement of sCD40L, and additional studies have had conflicting findings regarding the prognostic value of this marker. Methods and Results We measured levels of sCD40L in citrated plasma using an analytically validated automated immunoassay (Roche Diagnostics) in a large cohort of ACS patients (n = 2403) from the placebo arm of the OPUS TIMI-16 trial. No association was observed between elevated sCD40L levels and risk of death or myocardial infarction (MI) (Quartile 1, 8.0%; Quartile 2, 11.7%; Quartile 3, 8.2%; Quartile 4, 6.8%; P = 0.54) or risk of death, MI or heart failure at 10 months (Quartile 1, 9.9%; Quartile 2, 14.2%; Quartile 3, 10.9%; Quartile 4, 8.3%; P = 0.55). A comparison of plasma vs. serum measurements of sCD40L was performed on samples from a nested case–control analysis (n = 42) from within this cohort. Median sCD40L levels did not differ between cases and controls using plasma (0.23 ng/ml vs. 0.27 ng/ml, respectively; P = 0.82) or serum samples (0.64 vs. 0.77, respectively; P = 0.85). Serum samples consistently yielded elevated sCD40L measurements compared to plasma samples (median value 0.72 ng/ml vs. 0.25 ng/ml, respectively, P < 0.001). Conclusions The absence of an association between sCD40L and cardiovascular outcomes in a large cohort of patients with ACS raises concern regarding the reproducibility of clinical results with this novel biomarker. Despite a plausibly important role in the pathobiology of atherothrombosis, pre-analytic sources of variability may limit the practical clinical application of sCD40L.

Assessing the current role of platelet function testing.

Abstract: In vitro platelet function tests are commonly applied in research and offer justification for using antiplatelet therapy. However, studies assessing the ability of standardized platelet function tests to predict patients' clinical response to aspirin or clopidogrel have generated contradictory results. At this time, there is no standardized definition for resistance to antiplatelet therapy, and the appropriate treatment of patients who are hyporesponsive to these agents is not known. Although such tests have a role in research, their place in guiding therapy remains to be established, and prospective trials are urgently needed. The ideal platelet function test for clinical practice would be rapid, easy-to-use, inexpensive, and reliable.

JACC: Cardiovascular Interventions: The End of the Beginning

Abstract: ![Figure][1] In 1929, a unique event occurred in the then-young specialty of cardiology when Werner Forssmann performed the first cardiac catheterization—on himself! After what seemed to many as a one-time stunt, in 1941, Andre Cournand and Dickinson Richards began a systematic

Pleiotropic Effect of Lovastatin, With and Without Cholestyramine, in the Post Coronary Artery Bypass Graft (Post CABG) Trial

Abstract: This study evaluated patients in the Post Coronary Artery Bypass Graft (Post CABG) trial for evidence of statin pleiotropic effects in preventing atherosclerotic progression in saphenous vein grafts (SVGs). We studied 1,116 of the 1,351 patients in the Post CABG trial who were randomized to aggressive (low-density lipoprotein [LDL] cholesterol target

Antiplatelet strategies: evaluating their current role in the setting of acute coronary syndromes.

Abstract: Numerous clinical trials have established the value of antiplatelet therapies for acute coronary syndromes (ACS). Aspirin (ASA), thienopyridines (i.e., clopidogrel and ticlopidine) and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS and for the prevention of thrombotic complications of percutaneous coronary intervention (PCI). Clopidogrel is beneficial when administered before and after PCI, and is more effective when combined with either ASA or GP IIb/IIIa inhibitors in preventing post-PCI complications, coronary subacute stent thrombosis, and thrombotic events in general. It is currently unclear whether a higher loading dose of clopidogrel (600 mg) is better than the standard loading dose (300 mg), how long therapy should continue, and which maintenance dose is optimal. The role of the GP IIb/IIIa antagonists in ACS is less clear due to conflicting data from several studies with different patient populations. Currently, it appears that the use of GP IIb/IIIa antagonists might be most beneficial in high-risk ACS patients scheduled to undergo PCI, who demonstrate non-ST-segment elevation myocardial infarction and elevated troponin levels.

A perspective on the efficacy and safety of intensive antiplatelet therapy in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38.

Abstract: A primary goal of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON–TIMI 38) was to test the hypothesis that an agent achieving a greater and more consistent level of platelet inhibition (prasugrel) would improve clinical ischemic outcomes compared with standard approved doses of clopidogrel in patients at moderate to high risk with acute coronary syndromes (ACS) who underwent percutaneous coronary intervention (PCI). 1 The results of TRITON–TIMI 38 support this hypothesis, with a highly significant 19% relative reduction favoring prasugrel in the primary composite end point of cardiovascular (CV) death, nonfatal myocardial infarction (MI), and nonfatal stroke, from 12.1% to 9.9%, over a period of up to 15 months of followup. This reduction was observed at the cost of more serious bleeding. 2