Biomarkers of erythropoiesis response to intravenous iron in a crossover pilot study in unexplained anemia of the elderly.

Anemia is common in older adults, but often unexplained. Previously, we conducted a randomized, controlled trial of intravenous (IV) iron sucrose to study its impact on the 6-minute walk test and hemoglobin in older adults with unexplained anemia and ferritin levels of 20-200 ng/mL. In this report, we present for the first time the response of hemoglobin, as well as the dynamic response of biomarkers of erythropoiesis and iron indices, in a pooled analysis of the initially IV iron-treated group of 9 subjects and the subsequently IV iron treated 10 subjects from the delayed treatment group. We hypothesized that there would be a reproducible hemoglobin response from IV iron, and that iron indices and erythropoietic markers would reflect appropriate iron loading and reduced erythropoietic stress. To investigate the biochemical response of anemia to IV iron, we studied the dynamics of soluble transferrin receptor (STfR), hepcidin, erythropoietin (EPO), and iron indices over 12 weeks after treatment. In total, all 19 treated subjects were evaluable: 9 from initial treatment and 10 after cross-over. Hemoglobin rose from 11.0 to 11.7 g/dL, 12 weeks after initiating IV iron treatment of 1000 mg divided weekly over 5 weeks. We found early changes of iron loading after 1-2 IV iron dose: serum iron increased by 184 mcg/dL from a baseline of 66 mcg/dL, ferritin by 184 ng/mL from 68 ng/mL, and hepcidin by 7.49 ng/mL from 19.2 ng/mL, while STfR and serum EPO declined by 0.55 mg/L and 3.5 mU/mL from 19.2 ng/mL and 14 mU/mL, respectively. The erythroid response and evidence of enhanced iron trafficking are consistent with the hypothesis that IV iron overcomes iron deficient or iron-restricted erythropoiesis. These data provide new insight that iron-restricted erythropoiesis is a potential and targetable mechanism for patients diagnosed with unexplained anemia of the elderly and offers support for larger prospective trials of IV iron among anemic older adults of low to normal ferritin.

Effect of Torsemide vs Furosemide After Discharge on All-Cause Mortality in Patients Hospitalized With Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

Importance: Although furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide. Objective: To determine whether torsemide results in decreased mortality compared with furosemide among patients hospitalized for heart failure. Design, Setting, and Participants: TRANSFORM-HF was an open-label, pragmatic randomized trial that recruited 2859 participants hospitalized with heart failure (regardless of ejection fraction) at 60 hospitals in the United States. Recruitment occurred from June 2018 through March 2022, with follow-up through 30 months for death and 12 months for hospitalizations. The final date for follow-up data collection was July 2022. Interventions: Loop diuretic strategy of torsemide (n = 1431) or furosemide (n = 1428) with investigator-selected dosage. Main Outcomes and Measures: The primary outcome was all-cause mortality in a time-to-event analysis. There were 5 secondary outcomes with all-cause mortality or all-cause hospitalization and total hospitalizations assessed over 12 months being highest in the hierarchy. The prespecified primary hypothesis was that torsemide would reduce all-cause mortality by 20% compared with furosemide. Results: TRANSFORM-HF randomized 2859 participants with a median age of 65 years (IQR, 56-75), 36.9% were women, and 33.9% were Black. Over a median follow-up of 17.4 months, a total of 113 patients (53 [3.7%] in the torsemide group and 60 [4.2%] in the furosemide group) withdrew consent from the trial prior to completion. Death occurred in 373 of 1431 patients (26.1%) in the torsemide group and 374 of 1428 patients (26.2%) in the furosemide group (hazard ratio, 1.02 [95% CI, 0.89-1.18]). Over 12 months following randomization, all-cause mortality or all-cause hospitalization occurred in 677 patients (47.3%) in the torsemide group and 704 patients (49.3%) in the furosemide group (hazard ratio, 0.92 [95% CI, 0.83-1.02]). There were 940 total hospitalizations among 536 participants in the torsemide group and 987 total hospitalizations among 577 participants in the furosemide group (rate ratio, 0.94 [95% CI, 0.84-1.07]). Results were similar across prespecified subgroups, including among patients with reduced, mildly reduced, or preserved ejection fraction. Conclusions and Relevance: Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months. However, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence. Trial Registration: ClinicalTrials.gov Identifier: NCT03296813.

Ascertaining Death Events in a Pragmatic Clinical Trial: Insights From the TRANSFORM-HF Trial.

BACKGROUND: Death ascertainment can be challenging for pragmatic clinical trials that limit site follow-up activities to usual clinical care. METHODS AND RESULTS: We used blinded aggregate data from the ongoing ToRsemide comparison with furoSemide FOR Management of Heart Failure (TRANSFORM-HF) pragmatic clinical trial in patients with heart failure to evaluate the agreement between centralized call center death event identification and the United States National Death Index (NDI). Of 2284 total patients randomized through April 12, 2021, 1480 were randomized in 2018-2019 and 804 in 2020-2021. The call center identified 416 total death events (177 in 2018-2019 and 239 in 2020-2021). The NDI 2018-2019 final file identified 178 death events, 165 of which were also identified by the call center. The study's inter-rater reliability metric (Cohen's kappa coefficient, 0.920; 95% confidence interval, 0.889-0.951) demonstrates a high level of agreement. The time between a death event and its identification was less for the call center (median, 47 days; interquartile range, 11-103 days) than for the NDI (median, 270 days; interquartile range, 186-391 days). CONCLUSIONS: There is substantial agreement between deaths identified by a centralized call center and the NDI. However, the time between a death event and its identification is significantly less for the call center.

Pragmatic Design of Randomized Clinical Trials for Heart Failure: Rationale and Design of the TRANSFORM-HF Trial.

Randomized clinical trials are the foundation of evidence-based medicine and central to practice guidelines and patient care decisions. Nonetheless, randomized trials in heart failure (HF) populations have become increasingly difficult to conduct and are frequently associated with slow patient enrollment, highly selected populations, extensive data collection, and high costs. The traditional model for HF trials has become particularly difficult to execute in the United States, where challenges to site-based research have frequently led to modest U.S. representation in global trials. In this context, the TRANSFORM-HF (Torsemide Comparison with Furosemide for Management of Heart Failure) trial aims to overcome traditional trial challenges and compare the effects of torsemide versus furosemide among patients with HF in the United States. Loop diuretic agents are regularly used by most patients with HF and practice guidelines recommend optimal use of diuretic agents as key to a successful treatment strategy. Long-time clinical experience has contributed to dominant use of furosemide for loop diuretic therapy, although preclinical and small clinical studies suggest potential advantages of torsemide. However, due to the lack of appropriately powered clinical outcome studies, there is insufficient evidence to conclude that torsemide should be routinely recommended over furosemide. Given this gap in knowledge and the fundamental role of loop diuretic agents in HF care, the TRANSFORM-HF trial was designed as a prospective, randomized, event-driven, pragmatic, comparative-effectiveness study to definitively compare the effect of a treatment strategy of torsemide versus furosemide on long-term mortality, hospitalization, and patient-reported outcomes among patients with HF. (TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure [TRANSFORM-HF]; NCT03296813).

Stroke in Patients With Peripheral Artery Disease.

Background and Purpose- Predictors of stroke and transient ischemic attack (TIA) in patients with peripheral artery disease (PAD) are poorly understood. The primary aims of this analysis were to (1) determine the incidence of ischemic/hemorrhagic stroke and TIA in patients with symptomatic PAD, (2) identify predictors of stroke in patients with PAD, and (3) compare the rate of stroke in ticagrelor- and clopidogrel-treated patients. Methods- EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized 13 885 patients with symptomatic PAD to receive monotherapy with ticagrelor or clopidogrel for the prevention of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or ischemic stroke). Ischemic/hemorrhagic stroke and TIA were adjudicated and measured as incidence rates postrandomization and cumulative incidence (per patient-years). Post hoc multivariable competing risk hazards analyses were performed using baseline characteristics to determine factors associated with all-cause stroke in patients with PAD. Results- A total of 458 cerebrovascular events in 424 patients (317 ischemic strokes, 39 hemorrhagic strokes, and 102 TIAs) occurred over a median follow-up of 30 months, for a cumulative incidence of 0.87, 0.11, and 0.27 per 100 patient-years, respectively. Age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, geographic region, ankle-brachial index <0.60, prior amputation, and systolic blood pressure were independent baseline factors associated with the occurrence of all-cause stroke. After adjustment for baseline factors, the rates of ischemic stroke and all-cause stroke remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was no significant difference in the incidence of hemorrhagic stroke or TIA between the 2 treatment groups. Conclusions- In patients with symptomatic PAD, ischemic stroke and TIA occur frequently over time. Comorbidities such as age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, higher blood pressure, prior amputation, lower ankle-brachial index, and geographic region were each independently associated with the occurrence of all-cause stroke. Use of ticagrelor, as compared with clopidogrel, was associated with a lower adjusted rate of ischemic and all-cause stroke. Further study is needed to optimize medical management and risk reduction of all-cause stroke in patients with PAD. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01732822.

Ambulatory blood pressure in the dash diet trial: Effects of race and albuminuria.

We evaluated whether low-grade albuminuria or black race modulates ambulatory blood pressure (BP) or nocturnal BP response to the DASH diet. Among 202 adults enrolled in the DASH multicenter trial who were fed the DASH or control diet for 8 weeks, reductions in 24-hour daytime and nighttime SBP and DBP were significantly larger for DASH compared to control. Median changes in nocturnal BP dipping were not significant. Compared to urine albumin excretion of <7 mg/d, ≥7 mg/d was associated with larger significant median reductions in 24-hour SBP (-7.3 vs -3.1 mm Hg), all measures of DBP (24-hour: -5.9 vs -1.8 mm Hg; daytime: -9.9 vs -4.0 mm Hg; nighttime -9.0 vs -2.0 mm Hg), and with increased nocturnal SBP dipping (2.3% vs -0.5%). Black race was associated with larger median reduction in 24-hour SBP only (-5.5 vs -2.4 mm Hg). This analysis suggests greater effect of DASH on ambulatory BP in the presence of low-grade albuminuria.

Short-term effects of the DASH diet in adults with moderate chronic kidney disease: a pilot feeding study.

BACKGROUND: Although the Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure (BP) for adults with normal kidney function, evidence is lacking regarding its safety and efficacy in chronic kidney disease (CKD). We aimed to test the effects of the DASH diet on serum electrolytes and BP in adults with moderate CKD. METHODS: In a prospective before-after feeding study, 11 adults with an estimated glomerular filtration rate of 30-59 mL/min/1.73 m(2) and medication-treated hypertension were provided a reduced-sodium, run-in diet for 1 week followed by a reduced-sodium, DASH diet for 2 weeks. Changes in serum electrolytes and BP were compared pre-post DASH. RESULTS: Eleven participants underwent feeding; 1 completed 1 week and 10 completed 2 weeks of DASH. Compared with baseline, DASH modestly increased serum potassium at 1 week (mean ± standard deviation, +0.28 ± 0.4 mg/dL; P = 0.043) but had no significant effect on potassium at 2 weeks (+0.15 ± 0.28 mg/dL; P = 0.13). Serum bicarbonate was reduced (-2.5 ± 3.0 mg/dL; P = 0.03) at 2 weeks. Neither incident hyperkalemia nor new onset metabolic acidosis was observed. Clinic BP and mean 24-h ambulatory BP was unchanged. DASH significantly reduced mean nighttime BP (-5.3 ± 5.8 mmHg; P = 0.018), and enhanced percent declines in both nocturnal systolic BP (-2.1% to -5.1%; P = 0.004) and diastolic BP (-3.7% to -10.0%; P = 0.008). CONCLUSIONS: These pilot data suggest that a reduced-sodium DASH dietary pattern does not cause acute metabolic events in adults with moderate CKD and may improve nocturnal BP. Definitive studies are needed to determine long-term effects of DASH in CKD.

A prospective randomized wait list control trial of intravenous iron sucrose in older adults with unexplained anemia and serum ferritin 20-200 ng/mL.

Anemia is common in older persons and is associated with substantial morbidity and mortality. One third of anemic older adults have unexplained anemia of the elderly (UAE). We carried out a randomized, wait list control trial in outpatients with UAE and serum ferritin levels between 20 and 200 ng/mL. Intravenous iron sucrose was given as a 200-mg weekly dose for 5 weeks either immediately after enrollment (immediate intervention group) or following a 12-week wait list period (wait list control group). The primary outcome measure was changed in 6-minute walk test (6MWT) distances from baseline to 12 weeks between the two groups. Hematologic, physical, cognitive, and quality of life parameters were also assessed. The study was terminated early after 19 subjects enrolled. The distance walked in the 6MWT increased a mean 8.05±55.48 m in the immediate intervention group and decreased a mean 11.45±49.46 m in the wait list control group (p=0.443). The hemoglobin increased a mean 0.39±0.46 g/dL in the immediate intervention group and declined a mean 0.39±0.85 g/dL in the wait list control group (p=0.026). Thus, a subgroup of adults with UAE may respond to intravenous iron. Enrollment of subjects into this type of study remains challenging.

Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease.

BACKGROUND: Recombinant erythropoietin has become a routine component of care of patients with chronic kidney disease reducing the need for blood transfusions but raising the risks for cardiovascular events. We undertook this secondary analysis of subjects enrolled in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial to examine the interrelationships between epoetin-alfa maintenance doses utilized and achieved hemoglobin (Hb) irrespective of treatment target and randomized allocation. METHODS: We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m(2). To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have ≥1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis. RESULTS: Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point. CONCLUSIONS: In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent.

Impact of higher hemoglobin targets on blood pressure and clinical outcomes: a secondary analysis of CHOIR.

BACKGROUND: Targeting a higher hemoglobin in patients with chronic kidney disease leads to adverse cardiovascular outcomes, yet the reasons remain unclear. Herein, we sought to determine whether changes in erythropoiesis-stimulating agent (ESA) dose and in hemoglobin were predictive of changes in blood pressure (BP) and whether these changes were associated with cardiovascular outcomes. METHODS: In this secondary analysis of 1421 Correction of Hemoglobin and Outcomes in Renal Disease (CHOIR) participants, mixed model analyses were used to describe monthly changes in ESA dose and hemoglobin with changes in diastolic BP (DBP) and systolic BP (SBP). Poisson modeling was performed to determine whether changes in hemoglobin and BP were associated with the composite end point of death or cardiovascular outcomes. RESULTS: Monthly average DBP, but not SBP, was higher in participants in the higher hemoglobin arm. Increases in ESA doses and in hemoglobin were significantly associated with linear increases in DBP, but not consistently with increases in SBP. In models adjusted for demographics and comorbid conditions, increases in ESA dose (>0 U) and larger increases in hemoglobin (>1.0 g/dL/month) were associated with poorer outcomes [event rate ratio per 1000 U weekly dose per month increase 1.05, (1.02-1.08), P = 0.002 and event rate ratio 1.70 (1.02-2.85), P = 0.05, respectively]. However, increasing DBP was not associated with adverse outcomes [event rate ratio 1.01 (0.98-1.03), P = 0.7]. CONCLUSION: Among CHOIR participants, higher hemoglobin targets, increases in ESA dose and in hemoglobin were associated both with increases in DBP and with higher event rates; however, increasing DBP was not associated with adverse outcomes.

Effect of hemoglobin target on progression of kidney disease: a secondary analysis of the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial.

BACKGROUND: Conflicting relationships have been described between anemia correction using erythropoiesis-stimulating agents and progression of chronic kidney disease (CKD). This study was undertaken to examine the impact of target hemoglobin level on progression of kidney disease in the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial. STUDY DESIGN: Secondary analysis of a randomized controlled trial. SETTING & PARTICIPANTS: 1,432 participants with CKD and anemia. INTERVENTION: Participants were randomly assigned to target hemoglobin levels of 13.5 versus 11.3 g/dL with the use of epoetin alfa. OUTCOMES & MEASUREMENTS: Cox regression was used to estimate HRs for progression of CKD (a composite of doubling of creatinine level, initiation of renal replacement therapy, or death). Interactions between hemoglobin target and select baseline variables (estimated glomerular filtration rate, proteinuria, diabetes, heart failure, and smoking history) also were examined. RESULTS: Participants randomly assigned to higher hemoglobin targets experienced shorter time to progression of kidney disease in both univariate (HR, 1.25; 95% CI, 1.03-1.52; P = 0.02) and multivariable models (HR, 1.22; 95% CI, 1.00-1.48; P = 0.05). These differences were attributable to higher rates of renal replacement therapy and death for participants in the high hemoglobin arm. Hemoglobin target did not interact with estimated glomerular filtration rate, proteinuria, diabetes, or heart failure (P > 0.05 for all). In the multivariable model, hemoglobin target interacted with tobacco use (P = 0.04) such that the higher target had a greater risk of CKD progression for participants who currently smoked (HR, 2.50; 95% CI, 1.23-5.09; P = 0.01), which was not present for those who did not currently smoke (HR, 1.15; 95% CI, 0.93-1.41; P = 0.2). LIMITATIONS: A post hoc analysis; thus, cause and effect cannot be determined. CONCLUSIONS: These results suggest that a high hemoglobin target is associated with a greater risk of progression of CKD. This risk may be augmented by concurrent smoking. Further defining the mechanism of injury may provide insight into methods to optimize outcomes in anemia management.

A secondary analysis of the CHOIR trial shows that comorbid conditions differentially affect outcomes during anemia treatment.

The CHOIR trial in anemic patients with chronic kidney disease compared epoetin-alfa treatment with low (11.3 g/l) and high (13.5 g/l) hemoglobin targets on the composite end point of death, hospitalization for heart failure, stroke, and myocardial infarction. However, other anemia management trials in patients with chronic kidney disease found there was increased risk when hemoglobin is targeted above 13 g/dl. In this secondary analysis of the CHOIR trial, we compared outcomes among the subgroups of patients with diabetes and heart failure to describe the comparative relationship of treatment to these two different hemoglobin goals. By Cox regression analysis, there was no increased risk associated with the higher hemoglobin target among patients with heart failure. In patients without heart failure, however, the hazard ratio (1.86) associated with the higher target was significant. Comparing survival curves in an unadjusted model, patients with diabetes did not have a greater hazard associated with the higher target. Subjects without diabetes had a significantly greater hazard in the high as compared to the low target, but the interaction between diabetes and the target was not significant. We suggest that the increased risks associated with higher hemoglobin targets are not clinically apparent among subgroups with greater mortality risk. These differential outcomes underscore the need for dedicated trials in these subpopulations.

Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes.

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.

Correction of anemia with epoetin alfa in chronic kidney disease.

BACKGROUND: Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined. METHODS: In this open-label trial, we studied 1432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g per deciliter. The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke. RESULTS: A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P=0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event. CONCLUSIONS: The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life. (ClinicalTrials.gov number, NCT00211120 [ClinicalTrials.gov].).

Elevated creatine kinase-MB with normal creatine kinase predicts worse outcomes in patients with acute coronary syndromes: results from 4 large clinical trials.

BACKGROUND: The degree to which elevated creatine kinase (CK)-MB in the presence of normal CK is predictive of outcome is not well understood despite having been studied for decades. This analysis examined whether normal CK with elevated CK-MB in patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) is an independent predictor of worse outcomes. A concomitant goal was to contribute insight to the debate over how patients with NSTE ACS should be managed. METHODS: Data for 25,960 patients from the GUSTO IIb, PARAGON A and B, and PURSUIT trials were analyzed. Of these patients, 6402 were excluded from primary analysis because of missing (unmeasured) biomarkers. Patients with complete laboratory data (n = 19,558) were grouped by CK and CK-MB results. To confirm the primary analysis results, data from patients with missing biomarkers were used in an imputation model. RESULTS: Patients were categorized in 1 of 4 groups: normal CK + normal CK-MB; normal CK + elevated CK-MB; elevated CK + normal CK-MB; or elevated CK + elevated CK-MB. For the primary outcome, 180-day death, or myocardial infarction, Kaplan-Meier estimates were 14.9%, 20.8%, 14.5%, and 18.2%, respectively. Regardless of total CK, elevated CK-MB was associated with a 25% to 49% increased relative risk of worse outcomes. Findings from the analyses were verified by the multivariable model. CONCLUSIONS: CK-MB remains a reliable marker for myocardial necrosis and a strong predictor of worse prognosis. All patients with ACS should have CK-MB measurement to search for cardiac ischemia. Patients with elevated CK-MB should receive aggressive management commensurate with their increased risks.

Aspirin dose and six-month outcome after an acute coronary syndrome.

OBJECTIVES: This study was designed to compare the efficacy of low and intermediate aspirin doses in acute coronary syndromes. BACKGROUND: Little is known of the comparative efficacy of low and intermediate aspirin doses in this setting. METHODS: We compared six-month death, myocardial infarction (MI), and stroke in patients with unstable angina or acute MI discharged while receiving low (<150 mg) or intermediate (> or =150 mg) aspirin therapy in the GUSTO IIb and PURSUIT trials (n = 20,521). We used multivariable analysis and performed a propensity analysis in order to adjust for baseline imbalances between the groups. RESULTS: Aspirin doses <150 mg were prescribed to 29.9% (6,128) of patients. By six months, 6.4% of the patients (1,310 of 20,521) had a primary event, 6.2% of the patients receiving <150 mg and 6.6% of the patients receiving aspirin doses > or =150 mg (hazard ratio [HR] 1.06 [95% confidence interval (CI) 0.94 to 1.19], p = 0.35). After adjusting for baseline imbalances and the propensity score for discharge aspirin dose, there was no effect of aspirin dose on the composite end point at six months (HR 0.92 [95% CI 0.79 to 1.07], p = 0.28). However, the higher aspirin dose was associated with a reduction in six-month MI (HR 0.79 [95% CI 0.64 to 0.98], p = 0.03). The outcome was similar when patients were matched on the basis of the propensity score for aspirin dose (HR for death/MI/stroke 0.94 [95% CI 0.80 to 1.12], p = 0.51), although stroke occurred significantly more frequently among patients receiving the higher aspirin dose (HR 1.74 [95% CI 1.01 to 3.02] p = 0.05) and the effect on MI was no longer apparent. CONCLUSIONS: Although these data are non-randomized, they suggest that the aspirin dose upon discharge may influence the clinical course after unstable angina or acute MI.

Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival: results from the Do Tirofiban and ReoProGive Similar Efficacy Outcome Trial (TARGET).

OBJECTIVE: We sought to examine if clopidogrel treatment initiated before coronary stenting improved clinical outcomes among patients receiving aspirin and a glycoprotein (GP) IIb/IIIa inhibitor. BACKGROUND: Antiplatelet therapy plays a pivotal role in contemporary percutaneous coronary interventions (PCI). METHODS: Outcomes among 4,809 patients randomized to tirofiban or abciximab during PCI with stent placement were compared according to whether they received 300 mg of clopidogrel before PCI (93.1%) versus immediately after the procedure. RESULTS: The 30-day primary composite end point (death, myocardial infarction [MI], or urgent target vessel revascularization [TVR]) was lower among clopidogrel-pretreated patients (6.6% vs. 10.4%, p = 0.009), mainly because of reduction of MI (6.0% vs. 9.5%, p = 0.012). The benefit of clopidogrel pretreatment was sustained at six months (death, MI, any TVR: 14.6% vs. 19.8%, HR = 0.71, p = 0.010), and this was due mainly to lowering of death and MI (7.8% vs. 13.0%, p = 0.001). At one year, clopidogrel pretreatment was associated with a lower mortality rate (1.7% vs. 3.6%, p = 0.011). Because clopidogrel pretreatment was not randomized, multivariable and propensity analyses were performed. After adjusting for baseline heterogeneity, clopidogrel pretreatment was an independent predictor for death or MI at 30 days (HR = 0.63, p = 0.012) and at six months (HR = 0.61, p = 0.003), and survival at one year (HR = 0.53, p = 0.044). No excess in 30-day bleeding events was noted with clopidogrel pretreatment. CONCLUSIONS: Among patients undergoing coronary stent placement with aspirin and a GP IIb/IIIa inhibitor, clopidogrel pretreatment is associated with a reduction of death and MI irrespective of the type of GP IIb/IIIa inhibitor used.

Mortality benefit of beta blockade in patients with acute coronary syndromes undergoing coronary intervention: pooled results from the Epic, Epilog, Epistent, Capture and Rapport Trials.

The effects of beta blocker therapy in the settings of heart failure and coronary artery disease have been well described, although little data exist in patients presenting with acute coronary syndromes undergoing percutaneous coronary intervention. The current study will attempt to evaluate the efficacy of beta blocker therapy in this setting. Pooled data from five randomized, controlled trials of abciximab during coronary intervention were used to analyze the clinical efficacy of beta blocker therapy. The pooled analysis evaluated the end points of all-cause mortality, myocardial infarction, repeat revascularization, and the combined endpoint of death and myocardial infarction in 2,894 patients. At 30 days, death occurred in 12 of 1,939 (0.6%) patients receiving beta blocker therapy and in 19 of 955 (2.0%) patients not receiving beta blocker therapy, (P < 0.001). At 6 months, death occurred in 33 of 1,939 (1.7%) patients receiving beta blocker therapy and 35 of 955 (3.7%) not receiving beta blocker therapy, (P < 0.001). After creating a propensity model and adjusting for variables predictive of mortality in the multivariable analysis, beta blocker therapy continued to be associated with a significant reduction in mortality. The findings were similar to those shown for the effects of beta blocker therapy in separate subgroups of patients with unstable angina and acute myocardial infarction. This analysis demonstrates a lower short-term mortality in patients receiving beta blocker therapy who undergo percutaneous coronary intervention for unstable angina or acute myocardial infarction.

Prevalence of conventional risk factors in patients with coronary heart disease.

CONTEXT: It is commonly suggested that more than 50% of patients with coronary heart disease (CHD) lack any of the conventional risk factors (cigarette smoking, diabetes, hyperlipidemia, and hypertension). This claim implies that other factors play a significant role in CHD and has led to considerable interest in nontraditional risk factors and genetic causes of CHD. OBJECTIVE: To determine the prevalence of the 4 conventional risk factors among patients with CHD. DESIGN, SETTING, AND PATIENTS: In 2002-2003, we analyzed data for 122458 patients enrolled in 14 international randomized clinical trials of CHD conducted during the prior decade. Patients included 76716 with ST-elevation myocardial infarction, 35527 with unstable angina/non-ST-elevation myocardial infarction, and 10215 undergoing percutaneous coronary intervention. MAIN OUTCOME MEASURES: Prevalence of each conventional risk factor and number of conventional risk factors present among patients with CHD, compared between men and women and by age at trial entry. RESULTS: Among patients with CHD, at least 1 of the 4 conventional risk factors was present in 84.6% of women and 80.6% of men. In younger patients (men < or =55 years and women < or =65 years) and most patients presenting either with unstable angina or for percutaneous coronary intervention, only 10% to 15% of patients lacked any of the 4 conventional risk factors. This pattern was largely independent of sex, geographic region, trial entry criteria, or prior CHD. Premature CHD was related to cigarette smoking in men and cigarette smoking and diabetes in women. Smoking decreased the age at the time of CHD event (at trial entry) by nearly 1 decade in all risk factor combinations. CONCLUSIONS: In direct contrast with conventional thinking, 80% to 90% of patients with CHD have conventional risk factors. Although research on nontraditional risk factors and genetic causes of heart disease is important, clinical medicine, public health policies, and research efforts should place significant emphasis on the 4 conventional risk factors and the lifestyle behaviors causing them to reduce the epidemic of CHD.