Abstract The damage inflicted on the myocardium during acute myocardial infarction is the result of 2 processes: ischemia and subsequent reperfusion (ischemia/reperfusion injury). During the last 3 ...decades, therapies to reduce ischemic injury (mainly reperfusion strategies) have been widely incorporated into clinical practice. The remarkable reduction in death rates achieved with these therapies has resulted in a shift in emphasis from efforts to reduce mortality to a focus on tackling the downstream consequence of survival: post-infarction heart failure. Infarct size is the main determinant of long-term mortality and chronic heart failure, and thus, the possibility of limiting the extent of necrosis during an ST-segment elevation myocardial infarction is of great individual and socioeconomic value. After the great success of therapies to reduce ischemic injury, the time has come to focus efforts on therapies to reduce reperfusion injury, but in the recent few years, few interventions have successfully passed the proof-of-concept stage. In this review, we examine the past, present, and future therapies to reduce ischemia/reperfusion injury.
Summary Background Intracoronary stenting can improve procedural success and reduce restenosis compared with balloon angioplasty in patients with acute coronary syndromes, but can also increase the ...rate of thrombotic complications including stent thrombosis. The TRITON–TIMI 38 trial has shown that prasugrel—a novel, potent thienopyridine—can reduce ischaemic events compared with standard clopidogrel therapy. We assessed the rate, outcomes, and prevention of ischaemic events in patients treated with prasugrel or clopidogrel with stents in the TRITON–TIMI 38 study. Methods Patients with moderate-risk to high-risk acute coronary syndromes were included in our analysis if they had received at least one coronary stent at the time of the index procedure following randomisation in TRITON-TIMI 38, and were further subdivided by type of stent received. Patients were randomly assigned in a 1 to 1 fashion to receive a loading dose of study drug (prasugrel 60 mg or clopidogrel 300 mg) as soon as possible after randomisation, followed by daily maintenance therapy (prasugrel 10 mg or clopidogrel 75 mg). All patients were to receive aspirin therapy. Treatment was to be continued for a minimum of 6 months and a maximum of 15 months. Randomisation was not stratified by stents used or stent type. The primary endpoint was the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Stent thrombosis was assessed using Academic Research Consortium definitions, and analysis was by intention to treat. TRITON-TIMI 38 is registered with ClinicalTrials.gov , number NCT00097591. Findings 12 844 patients received at least one coronary stent; 5743 received only drug-eluting stents, and 6461 received only bare-metal stents. Prasugrel compared with clopidogrel reduced the primary endpoint (9·7 vs 11·9%, HR 0·81, p=0·0001) in the stented cohort, in patients with only drug-eluting stents (9·0 vs 11·1%, HR 0·82, p=0·019), and in patients with only bare-metal stents (10·0 vs 12·2%, HR 0·80, p=0·003). Stent thrombosis was associated with death or myocardial infarction in 89% (186/210) of patients. Stent thrombosis was reduced with prasugrel overall (1·13 vs 2·35%, HR 0·48, p<0·0001), in patients with drug-eluting stents only (0·84 vs 2·31%, HR 0·36, p<0·0001), and in those with bare-metal stents only (1·27 vs 2·41%, HR 0·52, p=0·0009). Interpretation Intensive antiplatelet therapy with prasugrel resulted in fewer ischaemic outcomes including stent thrombosis than with standard clopidogrel. These findings were statistically robust irrespective of stent type, and the data affirm the importance of intensive platelet inhibition in patients with intracoronary stents. Funding TRITON–TIMI 38 was supported by research grants from Daiichi Sankyo and Eli Lilly.
Background Vitamin K antagonists are the only oral anticoagulants approved for long-term treatment of patients with a cardiac valve replacement. Objective This study aims to test a new dosing regimen ...for dabigatran etexilate in patients with a mechanical bileaflet valve. Methods Patients aged ≥18 years and ≤75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation a mitral bileaflet valve >3 months before randomization, will be randomized between dabigatran etexilate or warfarin (in a ratio of 2:1) in an open-label design. Initial doses of dabigatran will be based on the estimated creatinine clearance, and the doses will be adjusted based on measuring trough dabigatran plasma levels to achieve levels ≥50 ng/mL at steady state. Doses will range between 150 mg twice a day and 300 mg twice a day. Warfarin management and target international normalized ratio will be according to current practice guidelines at the discretion of the treating physicians. The plan is to treat 270 patients with dabigatran etexilate for a total study population of approximately 405 patients. Clinical efficacy and safety outcomes will be analyzed in an exploratory manner. Conclusions RE-ALIGN is the first study to test an alternative to warfarin in patients with mechanical heart valves. A definitive phase III study will be planned based on the results of this study.
Abstract Purpose Short-term outcomes have been well characterized in acute coronary syndromes; however, longer-term follow-up for the entire spectrum of these patients, including ST-segment-elevation ...myocardial infarction, non-ST-segment-elevation myocardial infarction, and unstable angina, is more limited. Therefore, we describe the longer-term outcomes, procedures, and medication use in Global Registry of Acute Coronary Events (GRACE) hospital survivors undergoing 6-month and 2-year follow-up, and the performance of the discharge GRACE risk score in predicting 2-year mortality. Methods Between 1999 and 2007, 70,395 patients with a suspected acute coronary syndrome were enrolled. In 2004, 2-year prospective follow-up was undertaken in those with a discharge acute coronary syndrome diagnosis in 57 sites. Results From 2004 to 2007, 19,122 (87.2%) patients underwent follow-up; by 2 years postdischarge, 14.3% underwent angiography, 8.7% percutaneous coronary intervention, 2.0% coronary bypass surgery, and 24.2% were re-hospitalized. In patients with 2-year follow-up, acetylsalicylic acid (88.7%), beta-blocker (80.4%), renin-angiotensin system inhibitor (69.8%), and statin (80.2%) therapy was used. Heart failure occurred in 6.3%, (re)infarction in 4.4%, and death in 7.1%. Discharge-to-6-month GRACE risk score was highly predictive of all-cause mortality at 2 years (c-statistic 0.80). Conclusion In this large multinational cohort of acute coronary syndrome patients, there were important later adverse consequences, including frequent morbidity and mortality. These findings were seen in the context of additional coronary procedures and despite continued use of evidence-based therapies in a high proportion of patients. The discriminative accuracy of the GRACE risk score in hospital survivors for predicting longer-term mortality was maintained.
Prosthetic valve thrombosis (PVT) is one of the most serious long-term complications after heart valve replacement, and optimal treatment remains unclear. The investigators report clinical ...characteristics and outcome of all consecutive patients with PVT treated with urgent surgery or thrombolysis with recombinant tissue plasminogen activator at a single center from January 1988 to December 2008. Thirty-one patients (mean age 59 years, range 20 to 75, 19% men) were diagnosed with PVT a median of 11 years after valve replacement (range 4 months to 32 years). Affected valve positions were mitral in 17 (55%), aortic in 8 (26%), and tricuspid in 6 (19%), and all but 1 were mechanical valves. Eighteen patients underwent urgent surgery, with 2 deaths in the immediate perioperative phase and 2 recurrences (11%) of PVT over a median follow-up period of 76 months. Of 13 patients treated with thrombolysis, there was immediate clinical improvement after a single administration of recombinant tissue plasminogen activator in 12 (92%), of whom 8 (61%) showed complete response with normalization of echocardiographic findings. The only nonresponder was subsequently referred for urgent surgery. Over a median follow-up period of 18 months, recurrence of PVT was seen in 4 patients (31%), with 1 fatal event in a patient refusing further anticoagulation treatment 1 week after successful thrombolysis. Other complications in the recombinant tissue plasminogen activator group included 1 stroke, 1 transient ischemic attack, 1 hemorrhagic complication requiring surgery, and 2 peripheral embolic events with spontaneous resolution. In conclusion, thrombolysis is an attractive first-line therapy for patients with PVT, with clinical outcomes comparing favorably with the standard surgical approach.
Background Because acute occlusion of coronary arteries supplying the inferolateral myocardium frequently eludes standard 12-lead electrocardiogram (ECG) diagnosis, these patients may present as ...non–ST-segment elevation acute coronary syndromes (NSTE-ACS). Methods We examined culprit artery occlusion among 1,957 NSTE-ACS patients in the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network trial who underwent diagnostic coronary angiography. We compared baseline characteristics, electrocardiographic findings, in-hospital treatment, and long-term outcomes between patients with and without occluded culprit arteries. Results The culprit artery was occluded in 528 (27%) patients. Culprit lesions were more frequently identified in the inferolateral territory among patients with an occluded culprit artery (63%) compared with those with a nonoccluded artery (45%, P < .0001). Patients with an occluded culprit artery were younger, more often male, and more likely to have had a prior myocardial infarction. Despite similar in-hospital treatment, patients with an occluded culprit artery had larger infarcts (median peak creatine kinase–MB 4.3 vs 2.1 × upper limit of normal, P < .0001) and higher risk-adjusted 6-month mortality (hazard ratio 1.72, 95% CI 1.07-2.79). Conclusions More than 25% of NSTE-ACS patients had an occluded culprit artery on angiography. These patients may represent ST-segment elevation myocardial infarction equivalents; thus, improved early risk stratification techniques would help more rapidly triage these high-risk patients to an early invasive management strategy.
Objectives This study sought to review cardiac troponin (cTn) trends during non–ST-segment elevation acute coronary syndrome (NSTE ACS) in patients undergoing percutaneous coronary intervention (PCI) ...in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndromes) and SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) studies and to study the relationship between post-PCI cTn and mortality. Background The prognostic value of cTn post-PCI is controversial. In patients with NSTE ACS, it is especially difficult to distinguish between cTn elevations due to PCI or index myocardial infarction (MI). Methods Time and cTn (indexed by upper limit of normal ULN) data pairs were plotted for 10,199 patients and independently reviewed by 2 physicians to identify patients in whom post-PCI cTn elevation could be distinguished from that of index MI. Post-PCI cTn peak was identified for each plot, and its relationship with 1-year mortality was evaluated using Cox modeling, correcting for 15 clinical variables from the EARLY ACS 1-year mortality model (including baseline cTn). We used an identical methodology to assess the association between creatine kinase-myocardial band and 1-year mortality. Results Patients with cTn (re-)elevation post-PCI not evaluable were identified and excluded from further analysis (4,198 41% with cTn rising prior to PCI; 229 2% with missing cTn). Among the remainder (n = 5,772 57%), in the multivariable model, peak cTn post-PCI was associated with a 7% increase in mortality (hazard ratio HR for 10× ULN increase: 1.07, 95% confidence interval CI: 1.02 to 1.11; p = 0.0038). Peak post-PCI creatine kinase-myocardial band was significantly associated with 1-year mortality (HR for 1× ULN increase: 1.13, 95% CI: 1.05 to 1.21; p = 0.0013). Conclusions We used a methodology that differentiated post-PCI cTn (re-)elevation from that of presenting MI in more than one-half of patients with NSTE ACS undergoing PCI. This identified a highly significant relationship between post-PCI cTn and 1-year mortality, with implications for both incorporating a cTn post-PCI MI definition and preventing PCI-related myonecrosis.
Background In the TRACER trial, vorapaxar, a protease-activated receptor-1 antagonist, plus standard care in non–ST-segment elevation acute coronary syndrome (NSTE ACS) patients did not significantly ...reduce the primary composite end point but reduced a key secondary end point and significantly increased bleeding. History of peripheral artery disease (PAD) was a risk-enrichment inclusion criterion. We investigated the efficacy and safety of vorapaxar in NSTE ACS patients with documented PAD. Methods TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS. Results In total, 936 (7.2%) patients had a history of PAD. Ischemic events occurred more frequently among patients with PAD (25.3%) versus no PAD (12.2%, P < .001), and Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding was more common in PAD (9.1%) versus no PAD (5.0%, P = .004). Similar rates of the composite end point (cardiovascular death, myocardial infarction, or stroke) occurred in patients with PAD treated with vorapaxar and placebo (21.7% vs 24.8%, P interaction = .787). Patients with PAD treated with vorapaxar, when compared with placebo, also had a numerical reduction in peripheral revascularization procedures (8.1% vs 9.0%, P = .158) and a lower extremity amputation rate (0.9% vs 1.5%, P = .107). Vorapaxar increased Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding similarly in patients with PAD (hazard ratio 1.47, 95% CI 0.89-2.45) and without (hazard ratio 1.48, 95% CI 1.22-1.79; P interaction = .921). Conclusions Patients with NSTE ACS and PAD were at increased risk for ischemic events. Lower rates of ischemic end points, peripheral revascularization, and amputation with vorapaxar did not reach statistical significance but warrant further investigation. Vorapaxar increased bleeding in both patients with and without PAD at a similar magnitude of risk.
Objectives This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for ...Clinical Event Reduction in Acute Coronary Syndrome) study patients with non–ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Background Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Methods Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Results Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). Conclusions In non–ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome TRA·CER Study P04736AM3; NCT00527943 )
We evaluated the interaction between protease-activated receptor-1 antagonist vorapaxar and concomitant glycoprotein (GP) IIb/IIIa receptor inhibitors in patients with non–ST-segment elevation acute ...coronary syndromes who underwent PCI. In Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial, 12,944 patients with non–ST-segment elevation acute coronary syndromes were randomized to vorapaxar or placebo. Administration of GP IIb/IIIa receptor inhibitors was allowed at the treating physician's discretion. We investigated whether use of GP IIb/IIIa receptor inhibitors modified vorapaxar's effect on non–coronary artery bypass grafting (CABG)-related bleeding at 7 days and ischemic events at 30 days. In total, 7,455 patients underwent PCI during index hospitalization. Of these, 2,023 patients (27.1%) received inhibitors and 5,432 (72.9%) did not. Vorapaxar was associated with a numerically higher rate of non–CABG-related moderate/severe Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding at 7 days compared with placebo in those who did (1.3% vs 1.0%) and did not (0.6% vs 0.4%) receive GP IIb/IIIa receptor inhibitors. Ischemic end point rates at 30 days were not significantly lower with vorapaxar versus placebo. Increased rates of non-CABG GUSTO moderate/severe bleeding were observed in patients who received GP IIb/IIIa receptor inhibitors versus those who did not (adjusted hazard ratio HR 1.77, 95% confidence interval CI 0.43 to 7.35 in placebo arm; adjusted HR 2.02, 95% CI 0.62 to 6.61 in vorapaxar arm) and in those who received vorapaxar versus placebo (adjusted HR 1.54, 95% CI 0.36 to 6.56 in the GP IIb/IIIa group; adjusted HR 1.34, 95% CI 0.44 to 4.07 in the no–GP IIb/IIIa group). No interaction was found between vorapaxar and inhibitor use up to 7 days (P interaction = 0.89) nor at the end of the treatment (P interaction = 0.74); however, the event rate was low. Also, no interaction was observed for efficacy end points after PCI at 30 days or at the end of the treatment. In conclusion, GP IIb/IIIa receptor inhibitor use plus dual antiplatelet therapy in a population with non–ST-segment elevation myocardial infarction planned for PCI was frequent but did not interact with vorapaxar's efficacy or safety. Nonetheless, GP IIb/IIIa receptor inhibitors and vorapaxar were associated with increased bleeding risk, and their combined use may result in additive effects on bleeding rates.
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