The impact of renal dysfunction on outcomes in the ExTRACT-TIMI 25 trial.

OBJECTIVES: The ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction 25) trial provided the opportunity to evaluate the impact of renal dysfunction on outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and compare enoxaparin (ENOX) and unfractionated heparin (UFH). BACKGROUND: It is unclear how renal dysfunction influences the balance between benefit and risk of antithrombotic therapy. METHODS: In the ExTRACT-TIMI 25 trial, 20,479 patients were randomized to UFH or ENOX. A reduced ENOX dose was administered to patients age > or =75 years and those with an estimated creatinine clearance (CrCl) <30 ml/min. RESULTS: A powerful relationship was observed between the severity of renal dysfunction (per 10 ml/min decrement in CrCl) and death, stroke, intracranial hemorrhage, and major and minor bleeding (p < 0.001 for each). There was a progressive increase in the treatment benefit with ENOX on death or nonfatal myocardial infarction (p < 0.01) with better renal function. Net clinical benefit (death, nonfatal MI, or nonfatal major bleeding) was significantly superior with ENOX (p < 0.001) for patients with a CrCl >60 ml/min (79.1% of the study population). Major bleeding and intracranial hemorrhage did not differ for patients with preserved renal function (CrCl >90 ml/min), but in those with renal dysfunction there was a progressively greater increase in the risk of major and minor bleeding with ENOX. CONCLUSIONS: Enoxaparin was superior to UFH for the majority of subjects. With more severe renal dysfunction, the net clinical benefit between ENOX and UFH did not differ, despite the rise in adverse events in both treatment groups. Future studies should take renal dysfunction into account when assessing antithrombotic regimens.     

Percutaneous coronary intervention in patients receiving enoxaparin or unfractionated heparin after fibrinolytic therapy for ST-segment elevation myocardial infarction in the ExTRACT-TIMI 25 trial.

OBJECTIVES: We sought to evaluate whether enoxaparin (ENOX) is superior to unfractionated heparin (UFH) as adjunctive therapy for patients with ST-segment elevation myocardial infarction (STEMI) who receive fibrinolytic therapy and subsequently undergo percutaneous coronary intervention (PCI) by analyzing data from the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction 25) trial. BACKGROUND: Limited data are available on the use of ENOX compared with UFH as adjunctive therapy in STEMI patients treated with fibrinolytic therapy and subsequent PCI. METHODS: A total of 20,479 STEMI patients who received fibrinolytic therapy were randomized to a strategy of ENOX throughout index hospitalization or UFH for at least 48 h, with blinded study drug to continue if PCI was performed. The primary end point of death or recurrent MI through 30 days was compared for ENOX versus UFH among the patients who underwent subsequent PCI (n = 4,676). RESULTS: After initial fibrinolysis, fewer patients underwent PCI through 30 days in the ENOX versus the UFH group (22.8% vs. 24.2%; p = 0.027). Among patients who underwent PCI by 30 days, the primary end point occurred in 10.7% of ENOX and 13.8% of UFH patients (0.77 relative risk; p < 0.001). There were no differences in major bleeding for ENOX versus UFH (1.4% vs. 1.6%; p = NS). Results were similar when PCI was carried out in patients receiving blinded study drug during PCI (n = 2,178). CONCLUSION: Among patients treated with fibrinolytic therapy for STEMI who underwent subsequent PCI, ENOX administration was associated with a reduced risk of death or recurrent MI without difference in the risk of major bleeding. The strategy of ENOX support for fibrinolytic therapy followed by PCI is superior to UFH and provides a seamless transition from the medical management to the interventional management phase of STEMI without the need for introducing a second anticoagulant in the cardiac catheterization laboratory.     

Efficacy and safety of enoxaparin versus unfractionated heparin in patients with ST-segment elevation myocardial infarction also treated with clopidogrel.

OBJECTIVES: The purpose of this study was to determine the efficacy and safety of enoxaparin (ENOX) versus unfractionated heparin (UFH) in patients with ST-segment elevation myocardial infarction (STEMI) receiving fibrinolytic therapy with and without clopidogrel. BACKGROUND: The efficacy and safety of ENOX and clopidogrel given together in STEMI remains to be defined. METHODS: We compared the rates of major adverse cardiovascular events (MACE) as well as the rates of bleeding in medically managed patients randomized to ENOX versus UFH in the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction 25) trial, stratified by concomitant clopidogrel use. RESULTS: Enoxaparin significantly reduced the rate of the composite of death, recurrent myocardial infarction, myocardial ischemia, or stroke, compared with UFH, both in patients (n = 2,173) treated with clopidogrel (10.8% vs. 13.9%, adjusted odds ratio [OR(adj)] 0.70, p = 0.013) and in patients (n = 12,918) not treated with clopidogrel (13.3% vs. 15.3%, OR(adj) 0.85, p = 0.003) with no evidence of heterogeneity (p(interaction) = 0.21). The excess risk of TIMI major bleeding with ENOX versus UFH was numerically but not statistically significantly higher in patients treated with clopidogrel (2.7% vs. 1.0%) versus those who were not (2.1% vs. 1.2%) (p(interaction) = 0.61). Net clinical benefit (MACE and major bleeding) favored treatment with ENOX over UFH, either with concomitant clopidogrel (absolute risk reduction 2.4%, 95% confidence interval [CI] -0.5% to 5.3%) or without (absolute risk reduction 1.7%, 95% CI 0.5% to 3.0%) (p(interaction) = 0.61). CONCLUSIONS: In patients with STEMI receiving fibrinolytic therapy, the net benefit of ENOX is similar in patients who are and are not treated with clopidogrel. The totality of trial data suggest that the combination of a fibrinolytic, aspirin, clopidogrel, and ENOX offers an attractive pharmacologic reperfusion strategy in STEMI.     

Safety and effectiveness of enoxaparin following fibrinolytic therapy: Results of the Acute Myocardial Infarction (AMI)-QUEBEC registry

BACKGROUND:

Previous randomized controlled trials and meta-analyses demonstrated the superior efficacy of enoxaparin (ENOX) over unfractionated heparin (UFH) in patients with ST segment elevation myocardial infarction (STEMI). The external validity of randomized controlled trials may be limited by selective inclusion of patients who are younger and healthier than the ‘real-life’ population.

OBJECTIVE:

To evaluate the safety and effectiveness of ENOX compared with UFH in unselected STEMI patients.

METHODS:

The safety and effectiveness of ENOX and UFH were compared in STEMI patients who received fibrinolytic therapy at 17 Quebec hospitals in 2003.

RESULTS:

A total of 498 STEMI patients received systemic anticoagulation, with ENOX and UFH administered in 114 and 384 patients, respectively. There were no differences in baseline characteristics between the two patient groups. The rates of in-hospital major adverse cardiac or cerebral events were 11.4% in the ENOX group compared with 14.0% in the UFH group (P=0.51). In-hospital death or nonfatal reinfarction occurred in 7.9% of patients who received ENOX compared with 9.9% of patients who received UFH (P=0.52). Major bleeding occurred in 4.4% of patients who received ENOX versus 6.0% in patients who received UFH (P=0.51).

INTERPRETATION:

There was no significant difference in the rates of in-hospital adverse events in the ENOX group compared with the UFH group, when used in the real-life context. Larger observational studies may further confirm the safety, effectiveness and optimal duration of the administration of ENOX in unselected STEMI patients treated with fibrinolysis.     

A strategy of using enoxaparin as adjunctive antithrombin therapy reduces death and recurrent myocardial infarction in patients who achieve early ST-segment resolution after fibrinolytic therapy: the ExTRACT-TIMI 25 ECG study.

AIMS: To determine the relationship between a strategy of enoxaparin (ENOX), early ST-segment resolution (STRes), and clinical outcomes on patients with ST-segment elevation myocardial infarction (STEMI) after fibrinolysis. METHODS AND RESULTS: Baseline and 180 min ECGs were analysed in 3208 of the 20 479 patients in the ExTRACT-TIMI 25 trial, which randomifzed patients with STEMI to ENOX vs. unfractionated heparin (UFH) as adjunctive therapy. STRes was defined as complete (70%), partial (30-70%), or none (<30%). There was no evidence for a difference in STRes between the groups assigned to the ENOX or UFH (median 69.4 vs. 67.2%; P = 0.13). Among patients with complete STRes (n = 1100), ENOX significantly reduced death or non-fatal recurrent MI at 30 days when compared with UFH (4.4 vs. 9.9%; OR(adj) 0.39; P < 0.001), whereas there was no difference in patients with only partial or no STRes [14.2 vs. 12.5%; OR(adj) 1.0; P = 0.98 (n = 368) and 16.2 vs. 15.9%; OR(adj) 1.0; P = 0.97 (n = 830), P for interaction = 0.008]. CONCLUSION: When compared with UFH, a strategy of ENOX significantly reduces death or non-fatal recurrent MI in patients who achieved complete STRes, but not in patients with less STRes. These data suggest that a strategy of ENOX improves outcomes by preventing re-occlusion in patients achieving initial successful reperfusion after fibrinolytic therapy rather than by facilitating initial reperfusion.     

Deviation of activated partial thromboplastin time from optimal level after 12 hours of intravenous infusion of unfractionated heparin -- an independent predictor of recurrence and unfavorable 30-day prognosis in patients with myocardial infarction

Aim of the study was to assess significance of deviations of activated partial thromboplastin time (APTT) from optimal level (50-75 sec) after 48 hours of intravenous infusion of unfractionated heparin (UFH) in streptokinase treated patients with myocardial infarction (MI) for prognosis of nonfatal reinfarction and cumulative criterion comprising cardiac death, nonfatal MI and early postinfarction angina. Infusion of streptokinase (1,500,000 U in 30-60 min) was carried out after loading dose of aspirin (250 mg) and intravenous bolus (5,000 U) of UFH in 75 patients (age 34-76 years) admitted within 6 hours after onset of acute ST-elevation MI. UFH infusion was started prior to termination of administration of streptokinase and continued for 48 hours. During first 12 hours infusion rate was 1,000 or 800 U/hour in patients with body mass > or = 80 and < 80 kg, respectively. During initial 12 hours infusion rate was corrected if at 6 hours APTT was less than 40 or exceeded 150 sec. After 12 hours a nomogram was used for UFH dose adjustment according to APTT. Maximal number of optimal APTT values during UFH infusion just reached 50%. During first 12 hours prevailed values above 75 sec, after 24 and 36 hours -- values below 50 sec. Deviation of APTT from optimal level in 12 hours after onset of UFH infusion was the only independent predictor of nonfatal recurrent MI during following 30 days (relative risk [RR] 9.01, 95% confidence interval [CI]1.1 to 77.2; p=0.043). Independent predictors of cumulative criterion were level of risk of death according to TIMI scale (RR 1.47, 95% CI 1.-3 to 2.11; p=0.036) and deviation of APTT from optimal level in 12 hours after onset of UFH infusion (RR 3.24, 95%CI 1.05 to 10.5; p=0.046). It should be noted that rather than suboptimal excessive hypocoagulation by 12th hour of UFH infusion was associated with worse prognosis. APTT levels in 6, 24, and 36 hours of UFH infusion had no prognostic significance in relation to events assessed in the study.     

Outcome of urgent and elective percutaneous coronary interventions after pharmacologic reperfusion with tenecteplase combined with unfractionated heparin, enoxaparin, or abciximab

OBJECTIVES: The aim of this study was to evaluate percutaneous coronary intervention (PCI) in the Assessment of the Safety and Efficacy of New Thrombolytic Regimens (ASSENT-3) trial. BACKGROUND: In the ASSENT-3 trial, co-therapy with abciximab (ABC) or enoxaparin (ENOX) reduced ischemic complications after ST-elevation acute myocardial infarction treated with tenecteplase when compared with unfractionated heparin (UFH). The effect of these new co-therapies on the results of PCI is unknown. METHODS: Clinical outcomes in patients who received co-therapy with ABC, ENOX, or UFH and subsequently underwent an elective (n = 1,064) or urgent (n = 716) PCI in the ASSENT-3 trial were compared. RESULTS: No significant differences in clinical end points were observed in patients who underwent an elective PCI. A non-significant trend toward fewer in-hospital myocardial re-infarctions was seen with ABC and ENOX when compared with UFH (0.5% vs. 0.6% vs. 1.5%, respectively). The incidence of bleeding complications was similar in the three treatment arms. Significantly fewer ABC- and ENOX-treated patients needed urgent PCI compared with UFH (9.1% vs. 11.9% vs. 14.3%; p < 0.0001), but outcomes in these patients were in general less favorable (30-day mortality: 8.2% vs. 5.4% vs. 4.5%; 1-year mortality: 11.0% vs. 8.5% vs. 5.6%; in-hospital re-infarction: 3.9% vs. 2.5% vs. 2.7%; major bleeding complications: 8.8% vs. 7.0% vs. 3.4%). In pairwise comparisons with UFH, the higher one-year mortality and major bleeding rates after ABC were statistically significant (p = 0.045 and p = 0.012, respectively). CONCLUSIONS: Clinical outcomes after elective PCI were similar with the three antithrombotic co-therapies studied in ASSENT-3. Although fewer patients needed urgent PCI with ABC and ENOX, clinical outcomes were less favorable in this selected population, especially with ABC.     

Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis.

AIMS: To determine whether the low-molecular weight heparin enoxaparin remains favourable when compared with unfractionated heparin (UFH) among patients with acute coronary syndromes (ACS) when incorporating efficacy and safety of these adjunctive therapies using a net clinical endpoint. METHODS AND RESULTS: We performed a meta-analysis of randomized trials of enoxaparin vs. UFH in ST-elevation-MI (STEMI) or non-ST-elevation-ACS (NSTEACS) (n = 49,088 patients in 12 trials). The net clinical endpoint was defined as death, MI, or major bleeding by 30 days. Death or myocardial infarction (MI) was significantly reduced with enoxaparin when compared with UFH (9.8 vs. 11.4%, OR 0.84, P < 0.001). The net clinical endpoint occurred less frequently with enoxaparin than UFH (12.5 vs. 13.5%, OR 0.90, P = 0.051). Major bleeding was higher with enoxaparin (4.3 vs. 3.4%, OR 1.25, P = 0.019). Among STEMI trials, the net clinical endpoint was significantly lower with enoxaparin (OR 0.84, P = 0.015), but there was no difference in NSTEACS trials (OR 0.97). CONCLUSIONS: When compared with UFH, enoxaparin was associated with superior efficacy as adjunctive antithrombin therapy among >49 000 patients across the ACS spectrum. Although bleeding was increased with enoxaparin, this increase was offset by a reduction in death or MI. The net clinical benefit in favour of enoxaparin was evident among the STEMI population and was neutral among the NSTEACS population.     

Enoxaparin is superior to unfractionated heparin in patients with ST elevation myocardial infarction undergoing fibrinolysis regardless of the choice of lytic: an ExTRACT-TIMI 25 analysis.

AIMS: We compared outcomes of ST-elevation myocardial infarction (STEMI) patients randomized to a strategy of either enoxaparin or unfractionated heparin (UFH) to support fibrinolysis. METHODS AND RESULTS: In the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25 (ExTRACT-TIMI 25) trial, 20,479 patients undergoing fibrinolysis for STEMI with a fibrin-specific agent (N = 16,283) or streptokinase (SK) (N = 4139) were randomized to enoxaparin throughout their hospitalization or UFH for at least 48 h. The primary end point of death or nonfatal recurrent MI through 30 days occurred in 12.0% of patients in the UFH and 9.8% in the enoxaparin groups when treated with fibrin-specific lytics [odds ratio(adjusted) (OR(adj)) 0.78; 95% CI 0.70-0.87; P < 0.001] and 11.8 vs. 10.2%, respectively, when treated with SK (OR(adj) 0.83; 95% CI 0.66-1.04; P = 0.10; P(interaction) = 0.58). Major bleeding rates including intracranial hemorrhage within the fibrin-specific cohort were 1.2 and 2.0% in the UFH and enoxaparin groups, respectively (P < 0.001) and 2.0% in UFH and 2.4% in enoxaparin patients in the SK cohort (P = 0.16). Interaction tests between antithrombin- and lytic-type were non-significant (P = 0.20). Death, nonfatal MI, or major bleeding was significantly reduced with enoxaparin in the fibrin-specific cohort (OR(adj) 0.82; 95% CI 0.74-0.91; P < 0.001) and favoured enoxaparin in the SK cohort (OR(adj) 0.89; 95% CI 0.72-1.10; P = 0.29; P(interaction) = 0.53). CONCLUSION: The benefits of an enoxaparin strategy over UFH were observed in both SK and fibrin-specific-treated STEMI patients. Therefore, an enoxaparin strategy is preferred over UFH to support fibrinolysis for STEMI regardless of lytic agent.     

Comparison of safety and efficacy of bivalirudin versus unfractionated heparin in high-risk patients undergoing percutaneous coronary intervention (from the Anti-Thrombotic Strategy for Reduction of Myocardial Damage During Angioplasty-Bivalirudin vs Heparin study)

Bivalirudin, a direct thrombin inhibitor, is as effective as unfractionated heparin (UFH), with decreased bleeding in patients with acute coronary syndromes who undergo percutaneous coronary intervention (PCI). The aim of this study was to evaluate the effectiveness of bivalirudin versus UFH in selected PCI patients at high bleeding risk. Four hundred one consecutive patients who underwent PCI fulfilling ≥ 1 enrollment criterion (age >75 years, chronic renal failure, and diabetes mellitus) were randomized to bivalirudin (bolus 0.75 mg/kg followed by infusion during the procedure; n = 198) or UFH (75 IU/kg; n = 203). In the overall population, 39% were aged >75 years, 22% had renal failure, 63% had diabetes, and 29% had acute coronary syndromes. The primary efficacy end point was the 30-day incidence of major adverse cardiac events (cardiac death, myocardial infarction, stent thrombosis, or target vessel revascularization). The primary safety end point was the occurrence of any bleeding or entry-site complications after PCI. All patients were preloaded with clopidogrel 600 mg. Glycoprotein IIb/IIIa inhibitors were used at the operators' discretion. Thirty-day major adverse cardiac event rates were 11.1% in the bivalirudin group and 8.9% in the UFH group (p = 0.56); the primary efficacy end point was reached mainly because of periprocedural myocardial infarction; 1 patient in the bivalirudin group had stent thrombosis. Occurrence of the primary safety end point was 1.5% in the bivalirudin group and 9.9% in the UFH group (p = 0.0001); this benefit was essentially driven by the prevention of entry-site hematomas >10 cm (0.5% vs 6.9%, p = 0.002). In conclusion, Anti-Thrombotic Strategy for Reduction of Myocardial Damage During Angioplasty-Bivalirudin vs Heparin (ARMYDA-7 BIVALVE) indicates that bivalirudin, compared with UFH, causes significantly lower bleeding and has a similar incidence of major adverse cardiac events in patients with older age, diabetes mellitus, or chronic renal failure who undergo PCI.     

Routine Invasive Strategy in Elderly Patients with Non-ST Elevation Acute Coronary Syndrome: An Updated Systematic Review and Meta-analysis of Randomized Trials

Invasive treatment with coronary angiography is preferred approach for patients with non-ST elevation acute coronary syndrome (NSTE-ACS) compared to medical therapy alone. The results from the randomized clinical trials (RCT) that compared the invasive treatment strategy vs. conservative approach in the elderly (≥75 years) with NSTE-ACS has been inconsistent. To compare invasive and conservative strategies in the elderly (>75 years) with NSTE-ACS. We searched PubMed, Cochrane CENTRAL Register and ClinicalTrials.gov (inception through July 10, 2021) for RCTs comparing invasive and conservative strategies in the elderly with NSTE-ACS. We used random-effects model to calculate risk ratio (RR) with 95% confidence interval(CI). A total of 6 RCT including 2,323 patients were included in the meta-analysis. The median follow-up duration was 13.5 months. When invasive approach was compared to conservative strategy, it showed no difference in all-cause mortality in patients aged ≥75 years with NSTE-ACS (RR of 0.85; 95% CI 0.70–1.04; P = 0.12; I2 = 0%). There was significant reduction in MI (RR 0.59; 95% CI 0.49 0.71; P < 0.001; I2 = 0%) and unplanned revascularization (RR 0.30, 95% CI 0.17-0.53, P <0.001, I2 = 0%). Invasive strategy was associated with higher risk of major bleeding when compared to conservative treatment (RR 2.12, 95% CI 1.21-3.74, P = 0.009, I2 = 0%). Comparison of both strategies showed no significant difference in stroke (RR 0.75; 95% CI 0.38-1.46, P = 0.40; I2 = 0%). This updated meta-analysis suggests that in elderly patients (>75 years) with NSTE-ACS, a routine invasive strategy is associated with a reduction in MI and revascularization, while increasing the risk of major bleeding, but without difference in all-cause mortality and stroke.     

Revascularization algorithm in acute STEMI should take into account age

BACKGROUND: In the elderly patients, the optimal reperfusion strategy of acute ST-segment elevation myocardial infarction (STEMI) remains a topic of debate. Moreover, there is a lack of data regarding the effect of time to treatment (TT) on prognosis of STEMI in elderly patients. PURPOSE: The goal of our work was to analyze, in real life, the link between TT and 1-year mortality in patients with STEMI (> or =75 years) who were treated with thrombolysis (THL) or primary percutaneous coronary intervention (PCI). METHODS AND MATERIALS: Data were extracted from our university hospital prospective registry. Between 1995 and 2005, all patients who met the criteria (> or =75 years old, has had an acute STEMI <12 h, has been admitted directly into our cardiologic care unit, and has had a revascularization procedure) were included in the analysis. Using logistic regression, we studied the relation between TT and 1-year mortality for each strategy of reperfusion in patients with STEMI who were > or =75 years old. RESULTS: One hundred fifty-nine consecutive patients with STEMI <12 h were analyzed; 35 were treated with THL and 124 were treated with primary PCI. Mean age (+/-S.D.) was 80+/-4 years, and 56% of patients were men. In logistic regression analysis, TT was not associated to death after THL (P=.81), while it was positively correlated after PCI (P=.03). All-cause 1-year mortality was markedly higher in the THL group than in the PCI group (51.4% vs. 15.3%; P<.001). CONCLUSION: Our work suggests that the extrapolation of algorithm of revascularization used in younger patients is not appropriate for elderly patients. Specific algorithm of revascularization and recommendations are needed in elderly patients.     

Blood pressure as a predictor of cardiovascular events in the elderly: the William Hale Research Program

This study evaluates the association between blood pressure (BP) and the risk of developing cardiovascular disease (CVD) events in the elderly. The Morton Plant Mease Foundation has followed 4,008 elderly patients >64 years of age for at least 5 years. Systolic and diastolic blood pressure (SBP and DBP) was divided into categories. Cardiovascular disease events were classified as myocardial infarction, stroke, and CVD-related deaths reported from the National Death Index. Cox proportional hazard ratios were used to assess the relationship between BP and CVD events and controlled for weight, gender, smoker, and alcohol use. Ages <75 and >or=75 years were assessed separately. After 11.1 years of follow-up, elevated SBP (P=<0.0001) is strongly associated with developing a future CVD event; the relationship is linear and graded and holds for ages above and below 75 years. The frequency of CVD events was lowest in the SBP <120 mm Hg group. In subjects <75 years of age, DBP elevations were not a significant risk factor for CVD events. (relative risk (RR): DBP 70 to <80 mm Hg=0.92; DBP 80 to <90 mm Hg=0.88; DBP >or=90 mm Hg=1.02.) With subjects >or=75 years of age, a DBP between 80 and 90 is associated with the lowest significant risk for CVD (RR: DBP 70 to <80 mm Hg=0.74; DBP 80 to <90 mm Hg=0.59; DBP >or=90=0.71). In conclusion, these findings support the Joint National Committee on Hypertension recommendations for SBP in the elderly. Further studies are warranted to identify optimal DBP for the elderly at various ages.     

Heparin or enoxaparin anticoagulation for primary percutaneous coronary intervention

Objectives : The aim of this study was to compare efficacy and safety outcomes among patients receiving enoxaparin or unfractionated heparin (UFH) while undergoing percutaneous coronary intervention (PCI) for ST‐segment elevation myocardial infarction (STEMI). Background : Primary PCI (pPCI) for ST elevation has traditionally been supported by UFH. The low molecular weight heparin enoxaparin may provide better outcomes when used for pPCI. Methods : Consecutive eligible patients (580) undergoing pPCI enrolled in the prospective electronic Pitié‐Salpêtrière registry of ischemic coronary syndromes (e‐PARIS) registry were grouped according to whether they received UFH or enoxaparin as the sole anticoagulant. Logistic regression modeling, propensity‐weighted adjustment, and sensitivity analyses were used to evaluate efficacy and safety endpoints for enoxaparin vs. UFH. Results : Enoxaparin was administered to 346 patients and UFH to 234 without ACT or anti‐Xa guided dose adjustment. PCI was performed through the radial artery in 90%, with frequent (75%) use of GPIIb/IIIa antagonists. Patients receiving enoxaparin were more likely to be therapeutically anticoagulated during the procedure (68% vs. 50%, P < 0.0001) and were less likely to experience death or recurrent myocardial infarction (MI) in hospital (adjusted OR 0.28 95% CI (0.12–0.68) or by 30 days (adjusted OR 0.35 95% CI 0.16–0.81). All cause mortality was also reduced in hospital (adjusted OR 0.32, 95% CI (0.12–0.85) and to 30 days (adjusted OR 0.40 95% CI 0.17–0.99). Other ischemic endpoints were similarly reduced with enoxaparin. Thrombolysis in myocardial infarction (TIMI) major bleeding events were numerically fewer among patients receiving enoxaparin (1.2% vs. 2.6%, P = 0.2). Conclusions : In patients with STEMI presenting for PCI, enoxaparin was associated with a reduction in all ischemic complications, more frequent therapeutic anticoagulation, and no increase in major bleeding when compared against unfractionated heparin. © 2010 Wiley‐Liss, Inc.     

Reperfusion strategies for acute myocardial infarction in the elderly: benefits and risks

The optimal reperfusion strategy in elderly patients with ST-segment elevation myocardial infarction (STEMI) remains a topic of debate. This lack of consensus stems from the exclusion or under-representation of the elderly in clinical trials. This review evaluates the available literature pertaining to reperfusion therapy for the treatment of STEMI in the elderly. We identified all published studies evaluating the effectiveness of thrombolytic therapy, primary percutaneous coronary intervention (PCI), or adjunctive therapies to reperfusion by conducting an electronic search of MEDLINE through December 2003. Meta-analysis of clinical trials suggests a survival benefit of thrombolytic therapy in the elderly with STEMI, whereas some observational studies have raised concerns about the lack of short-term benefit or possibility of harm with thrombolysis. However, most observational studies demonstrate improved intermediate-term survival with thrombolysis. In contrast, multiple clinical trials and observational studies indicate improved survival and low risk of stroke with primary PCI compared with thrombolysis in elderly patients with STEMI. Information on the efficacy of newer antithrombotic agents as adjunct to thrombolysis or primary PCI is scarce. Available data suggest an increased risk of intracerebral bleeding with the combination of a fibrin-specific agent and a glycoprotein IIb/IIIa receptor antagonist in patients >75 years of age. Clearly targeted large-scale clinical trials are needed to evaluate the relative merits of available reperfusion strategies as well as newer antithrombotic adjunctive therapies in the elderly with STEMI.     

Enoxaparin in the treatment of deep vein thrombosis with or without pulmonary embolism: an individual patient data meta-analysis

STUDY OBJECTIVES: Low-molecular-weight heparins have been compared with unfractionated heparin (UFH) for treatment of deep vein thrombosis (DVT). However, a comparison of their efficacy in the presence or absence of pulmonary embolism (PE) has not been studied. We estimated the efficacy and safety of enoxaparin vs UFH in patients with proximal DVT with/without symptomatic PE using a meta-analysis of individual data from randomized controlled trials. DESIGN AND SETTING: Randomized controlled trials were identified from MEDLINE, EMBASE, abstracts from international meetings on venous thromboembolism (VTE), previous meta-analyses, and trial data provided by the sponsor. PARTICIPANTS: For inclusion, randomized controlled trials had to be properly randomized; include patients with objectively diagnosed DVT; compare enoxaparin twice daily with UFH; use objective methods to assess recurrent symptomatic VTE, major bleeding, and death at 3 months; and include blind evaluation of clinical events. MEASUREMENTS: A meta-analysis was performed using the logarithm of the relative risk (RR) method. Enoxaparin in DVT treatment with/without symptomatic PE was considered noninferior to UFH for preventing VTE at 3 months if the upper limit of the 95% confidence interval (CI) of the RR (enoxaparin/UFH) was lower than a prespecified noninferiority margin (1.61). No increase in major bleeding or mortality should be observed. RESULTS: The meta-analysis included individual data from three randomized controlled trials (749 patients and 754 patients in the enoxaparin and UFH groups, respectively). The observed RR (enoxaparin/UFH) of VTE was 0.81 (95% CI, 0.52 to 1.26) for the intention-to-treat population (RR, 0.70; 95% CI, 0.43 to 1.13; for per-protocol analysis). Results did not differ for patients with clinical PE (235 patients; RR, 0.84) and without clinical PE (1,268 patients; RR, 0.71), with a nonsignificant heterogeneity test between groups (p = 0.76). A trend in favor of enoxaparin was observed for reduced mortality and major bleeding. CONCLUSIONS: The efficacy and safety of enoxaparin vs UFH for DVT treatment is not modified by the presence of symptomatic PE.     

Safety and low molecular weight heparin in older people in a hospital with ambulatory care

To examine major bleeding and mortality rates of low molecular weight heparin (LMWH) and unfractionated heparin (UFH) for patients with pulmonary embolism (PE) and/or deep vein thrombosis (DVT), a retrospective review of the medical records for 286 patients who presented at a local hospital with PE and/or DVT during the period November 2002-August 2003 was performed. Data collected: presence of co-morbidities, concurrent medications, presence, site and severity of bleeding, outcome. Of all the patients, 50.7% received LMWH plus warfarin, 21.0% received UFH plus LMWH plus warfarin, 14.0% received UFH and warfarin, and 9.8% received LMWH only. There were nine minor bleeds and six major bleeds, which resulted in four deaths. Being a hospitalized patient and being age > or =70 years were associated with a major bleed (p<0.05). For hospital inpatients age > or =70 years on UFH and LMWH the number of major bleeds/1000 patient days was 18.9 and 9.2, respectively. The major bleeding rate is comparable if not better than that reported in the literature in our hospital setting where nearly half of the anticoagulation services were provided as ambulatory care. The increased rate of bleeding in the elderly we found is consistent with the findings of previous studies.     

A high-value cost conscious approach to minimize heparin induced thrombocytopenia antibody (HITAb) testing using the 4T score

Unfractionated heparin (UFH) plasma protein binding and elimination might be impaired in patients with chronic kidney disease (CKD—defined as creatinine clearance <60 ml/min). It is currently unknown at which UFH bolus dose persistent prolongation of activated partial thromboplastin time (aPTT) occurs in ST-segment elevation myocardial infarction (STEMI) patients with CKD. We investigated the effect of different UFH bolus doses on the first aPTT measured within 6 and 12 h after PPCI in 1071 STEMI patients with and without CKD undergoing primary percutaneous coronary intervention (PPCI) between 1-1-2003 and 31-07-2008. In the first 6 h after PPCI, aPTT ratio was 5.1 for patients with CKD versus 3.4 for those without (p < 0.001). The proportion of patients with markedly high aPTTs (aPTT ratio ≥ 4 times control) increased with increasing heparin bolus and beyond 130 IU/kg there was a marked difference between patients with and without CKD (74.1 and 42.3 % respectively, p < 0.001). By multivariable analysis, CKD was associated with an increased risk of markedly high aPTTs (odds ratio (OR) 2.04; 95 % confidence interval (CI) 1.27–3.27), driven largely by an increased risk of aPTT prolongation in patients treated with UFH boluses ≥130 IU/kg (OR 3.69; 95 % CI 1.85–7.36; p for interaction = 0.009). In conclusion, CKD is associated with severe persistent aPTT prolongation in STEMI patients undergoing PPCI, possibly due to impaired plasma protein binding and reduced UFH elimination. A lower heparin bolus dose might result in lower aPTTs and less bleeding complications in patients with CKD undergoing PPCI.     

Bleeding risk and outcomes of Bivalirudin versus Glycoprotein IIb/IIIa inhibitors with targeted low-dose unfractionated Heparin in patients having percutaneous coronary intervention for either stable or unstable angina pectoris

For patients undergoing elective percutaneous coronary intervention (PCI), procedural anticoagulation with bivalirudin was previously shown to significantly reduce bleeding complications at the cost of a modest increase in ischemic events compared with unfractionated heparin (UFH) and glycoprotein IIb/IIIa inhibitors (GPIs). However, the excess bleeding in patients treated with UFH and GPIs may have been caused by excessively high UFH doses and increased activated clotting times. This study sought to determine the bleeding risk of targeted low-dose UFH with GPIs compared with bivalirudin in patients undergoing elective PCI. Of 1,205 patients undergoing elective PCI, 602 underwent PCI with adjunctive UFH and GPIs with the UFH dose targeted to an activated clotting time of approximately 250 seconds, and 603 patients matched for baseline characteristics underwent PCI with bivalirudin. Outcomes were analyzed for major bleeding (hematocrit decrease >15%, gastrointestinal bleed, or major hematoma) and 6-month major adverse cardiac events (death, myocardial infarction, and target-lesion revascularization). The maximum activated clotting time achieved was 261.7 +/- 61.6 seconds in the UFH/GPI group and 355.4 +/- 66.6 in the bivalirudin group (p <0.001). In-hospital major bleeding rates were similar between groups (1.8% UFH/GPI vs 1.7% bivalirudin; p = 0.83), as were transfusion requirements (1.2% UFH/GPI vs 0.5% bivalirudin; p = 0.61). The 6-month major adverse cardiac event rate was also similar between groups (9.5% UFH/GPI vs 9.0% bivalirudin; p = 0.81). In conclusion, there were no significant differences in major bleeding and 6-month major adverse cardiac events for patients undergoing elective PCI treated with targeted low-dose UFH and GPIs compared with those treated with bivalirudin.     

Non-vitamin K antagonist oral anticoagulants in elderly patients with atrial fibrillation: A systematic review with meta-analysis and trial sequential analysis

Background: Elderly population is known to be associated with polymedication, comorbidities and altered drug pharmacokinetics. However, the most adequate oral anticoagulant, attending to its relative efficacy and safety, remains unclear.Methods: We searched for phase III randomized controlled trials (MEDLINE, Cochrane Library, SciELO collection and Web of Science) comparing novel non-vitamin K antagonist oral anticoagulants (NOACs) with Vitamin K antagonists (VKA) in the elderly population (≥75 years-old) in atrial fibrillation (AF). Risk ratios (RR) were calculated using a random effects model. Trial sequential analysis (TSA) was performed in statistically significant results to evaluate whether cumulative sample size was powered.Results: Four trials rendered data about elderly (≥75 years-old) and younger patients (<75 years-old) with AF. NOACs demonstrated a 30% significant risk reduction (RR 0.70, 95% CI: 0.61 to 0.80) in elderly patients compared to VKA, without heterogeneity across studies (I² = 0%). The TSA showed that cumulative evidence of this subgroup exceeded the minimum information size required for the risk reduction. In younger patients, VKA and NOACs shared a similar risk of stroke and systemic embolism (RR 0.97, 95% CI: 0.79 to 1.18). Regarding major bleeding risk in the elderly, the overall comparative risk of NOACs was not different from VKA (RR 0.91, 95% CI: 0.72 to 1.16; I² = 86%).Conclusions: NOACs reduce significantly the risk of stroke and systemic embolism in elderly patients without increasing major bleeding events. The dimension of stroke risk reduction was significantly higher in the elderly than in younger adults.