Yinggan Zheng

Applying novel methods to assess clinical outcomes: insights from the TRILOGY ACS trial.

AIMS Several methods provide new insights into understanding clinical trial composite endpoints, using both conventional and novel methods. The TRILOGY ACS trial is used as a contemporary example to prospectively compare these methods side by side. METHODS AND RESULTS The traditional time-to-first-event, Andersen-Gill recurrent events method, win ratio, and a weighted composite endpoint (WCE) are compared using the randomized, active-control TRILOGY ACS trial. This trial had a neutral result and randomized 9326 patients managed without coronary revascularization within 10 days of their acute coronary syndrome to receive either prasugrel or clopidogrel and followed them for up to 30 months. The traditional composite, win ratio, and WCE demonstrated no significant survival advantage for prasugrel, whereas the Andersen-Gill method demonstrated a statistical advantage for prasugrel [hazard ratio (HR), 0.86 (95% CI, 0.72-0.97)]. The traditional composite used 73% of total patient events; 40% of these were derived from the death events. The win ratio used 66% of total events; deaths comprised 57% of these. Both Andersen-Gill and WCE methods used all events in all participants; however, with the Andersen-Gill method, death comprised 41% of the proportion of events, whereas with the WCE method, death comprised 64% of events. CONCLUSION This study addresses the relative efficiency of various methods for assessing clinical trial events comprising the composite endpoint. The methods accounting for all events, in particular those incorporating their clinical relevance, appear most advantageous, and may be useful in interpreting future trials. This clinical and statistical advantage is especially evident with long-term follow-up where multiple non-fatal events are more common. CLINICAL TRIAL REGISTRATION NCT00699998.

Sitagliptin and risk of fractures in type 2 diabetes: Results from the TECOS trial.

To examine fracture incidence among participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).

The long-term effects of dietary sodium restriction on clinical outcomes in patients with heart failure. The SODIUM-HF (Study of Dietary Intervention Under 100 mmol in Heart Failure): A pilot study

AIMS To determine the feasibility of conducting a randomized controlled trial comparing a low-sodium to a moderate-sodium diet in heart failure (HF) patients. METHODS AND RESULTS Patients with HF (New York Heart Association classes II-III) were randomized to low (1500 mg/d) or moderate-sodium (2300 mg/d) diet. Dietary intake was evaluated using 3-day food records. The end points were changes in quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores and B-type natriuretic peptide (BNP) levels from baseline to 6 months of follow-up presented as medians [25th, 75th percentiles]. Thirty-eight patients were enrolled (19/group). After 6 months, median sodium intake declined from 2137 to 1398 mg/d in the low-sodium and from 2678 to 1461 mg/d in the moderate-sodium diet group. Median BNP levels in the low-sodium diet group declined (216-71 pg/mL, P = .006), whereas in the moderate-sodium diet group, there was no change in BNP (171-188 pg/mL, P = .7; P = .17 between groups). For 6 months, median KCCQ clinical score increased in both groups (63-75 [P = .006] in the low-sodium diet group and 66-73 [P = .07] in the moderate-sodium group; P = .4 between groups). At 6 months, a post hoc analysis based on the dietary sodium intake achieved (> or ≤ 1,500 mg/d) in all patients showed an association between a sodium intake ≤ 1,500 mg/d and improvement in BNP levels and KCCQ scores. CONCLUSIONS A dietary intervention restricting sodium intake was feasible, and achievement of this sodium goal was associated with lower BNP levels and improved quality of life in patients with HF.

Baseline Q waves as a prognostic modulator in patients with ST-segment elevation: insights from the PLATO trial

Background: Baseline Q waves may provide additional value compared with time from the onset of symptoms in predicting outcomes for patients with ST-segment elevation. We evaluated whether baseline Q waves superseded time from symptom onset as a prognostic marker of one-year mortality in patients with ST-segment elevation acute coronary syndrome. Our study was derived from data from patients undergoing primary percutaneous coronary intervention within 24 hours in the PLATelet inhibition and patient Outcomes trial Methods: Q waves on the baseline electrocardiogram were evaluated by a blinded core laboratory. We assessed the associations between baseline Q waves and time from symptom onset to percutaneous coronary intervention with peak biomarkers, ST-segment resolution on the discharge electrocardiogram, and one-year all-cause and vascular mortality. Results: Of 4341 patients with ST-segment elevation, 46% had baseline Q waves. Compared to those without Q waves, those with baseline Q waves were older, more frequently male, had higher heart rates, more advanced Killip class and had a longer time between the onset of symptoms and percutaneous coronary intervention. They also had higher one-year all-cause mortality than patients without baseline Q waves (baseline Q waves: 4.9%; no baseline Q waves: 2.8%; hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.29–2.45, p < 0.001). Complete ST-segment resolution was greatest and all-cause mortality lowest among those with symptom onset three hours or less before percutaneous coronary intervention and no baseline Q waves. After multivariable adjustment, baseline Q waves, but not time from symptom onset, were associated with a significant increase in all-cause mortality (adjusted HR 1.42, 95% CI 1.10–2.01, p = 0.046) and vascular mortality (adjusted HR 1.58, 95% CI 1.09–2.28, p = 0.02). Interpretation: The presence of baseline Q waves provides useful additional prognostic insight into the clinical outcome of patients with ST-segment elevation. Clinical Trials.gov registration no. NCT00391872

Dietary fatty acids intake and mortality in patients with heart failure

OBJECTIVE Dietary strategies in heart failure (HF) are focused on sodium and fluid restriction to minimize the risk for acute volume overload episodes. However, the importance of dietary factors beyond sodium intake in the prognosis of the disease is uncertain. The purpose of this study was to evaluate the association of macro- and micronutrients intake on 1-y mortality in patients with HF. METHODS A secondary analysis of 203 patients with chronic HF enrolled in a randomized trial of sodium reduction was completed. Patients with a complete 3-d food record at baseline were included in this analysis (N = 118); both control and intervention arms were combined. Three-d mean dietary intake was estimated. Cox multivariable regression analysis was used to evaluate the association between dietary factors and 1-y mortality. RESULTS Among the 118 included patients, 54% were men, median (25th-75th percentiles) age 66 y (52-75 y), median ejection fraction 45% (30%-60%), and ischemic etiology present in 49% of patients. The association with 1-y mortality was significant for both polyunsaturated fatty acids (PUFA; adjusted hazard ratio [HR], 0.67; 95% confidence interval [CI]. 0.51-0.86 for intake as percentage of daily energy) and saturated fatty acids (SFA; adjusted HR, 1.15; 95% CI, 1.03-1.30 for intake as percentage of daily energy). Median of intake as percentage of daily energy was 5.3% for PUFAs and 8.2% for SFAs. CONCLUSIONS Intake of PUFAs and SFAs was independently associated with 1-y all-cause mortality in patients with chronic HF. Limiting dietary SFA and increasing PUFA intake may be advisable in this population.

Aborted myocardial infarction in ST-elevation myocardial infarction: insights from the STrategic Reperfusion Early After Myocardial infarction trial

Background We evaluated the prespecified endpoint, aborted myocardial infarction (AbMI), according to the use of a pharmacoinvasive (PI) strategy versus primary percutaneous coronary intervention (PCI) in 1754 patients randomised within 3 h of symptom onset in the STrategic Reperfusion Early After Myocardial infarction (STREAM) trial. Methods Based on sequential ECGs and biomarkers, AbMI was defined as ST-elevation resolution ≥50% (90 min posttenecteplase (TNK) in the PI arm or 30 min postprimary PCI) with minimal biomarker rise. Results In the PI arm 11.1% (n=99) had AbMI versus 6.9% (n=59) in primary PCI arm (p<0.01). In a multivariable model, AbMI patients overall had less baseline ΣST-deviation, fewer baseline Q-waves and shorter total ischaemic times. PI AbMI patients had faster time to TNK (90 vs 100 min, p=0.015): total ischaemic time was 100 min longer in primary PCI AbMI patients and no difference in ischaemic time existed between AbMI and non-AbMI patients within this group. Although no significant interaction between treatment and AbMI on the composite endpoint of death/shock/congestive heart failure/recurrent MI occurred (p=0.292), PI AbMI patients had a lower incidence in this endpoint than non-AbMI patients (5.1 vs 12%, p=0.038); this was not evident in primary PCI patients. Forty-five patients (ie, 2.5%) had masquerading MI with minimal biomarker elevation and no evolution in baseline ST-elevation. Conclusions A PI strategy of early fibrinolysis more frequently aborts MI than primary PCI. Such PI patients had more favourable outcomes as compared with non-AbMIs. Diligent review of ECG evolution in STEMI distinguishes AbMI from infarct masquerade. Clinical Trials.gov ID NCT00623623.

Providing Rapid Out of Hospital Acute Cardiovascular Treatment 4 (PROACT‐4)

Background Whether prehospital point‐of‐care (POC) troponin further accelerates the time to diagnosis in patients with chest pain (CP) is unknown. We conducted a randomized trial of POC‐Troponin testing in the ambulance. Methods and Results Patients with chest pain presenting by ambulance were randomized to usual care (UC) or POC‐Troponin; ST‐elevation myocardial infarction patients or those with noncardiovascular symptoms were excluded. Pre‐hospital high‐sensitivity troponin was analyzed on a POC device and available to the paramedic and emergency department (ED) staff. The final diagnosis was centrally adjudicated. The primary endpoint was time from first medical contact to discharge from ED or admission to hospital. We randomized 601 patients in 19 months; 296 to UC and 305 to POC‐Troponin. After ambulance arrival, the first troponin was available in 38 minutes in POC‐Troponin and 139 minutes in UC. In POC‐Troponin, the troponin was >0.01 ng/mL in 17.4% and >0.03 ng/mL in 9.8%. Patients spent a median of 9.0 hours from first medical contact to final disposition, and 165 (27.4%) were admitted to the hospital. The primary endpoint was shorter in patients randomized to POC‐Troponin (median 8.8 hours [6.2–10.8] compared to UC (median 9.1 hours [6.7–11.2]; P=0.05). There was no difference in the secondary endpoint of repeat ED visits, hospitalizations, or death in the next 30 days. Conclusions In this broad population of patients with CP, ambulance POC‐Troponin accelerated the time to final disposition. Enhanced and more cost‐effective early ED discharge of the majority of patients with CP calling 911 is an unrealized opportunity. Clinical Trial Registration URL: https://www.ClinicalTrials.gov/. Unique identifier: NCT01634425.

Reduced dose tenecteplase and outcomes in elderly ST-segment elevation myocardial infarction patients: Insights from the STrategic Reperfusion Early After Myocardial infarction trial

BACKGROUND Elderly patients with ST-segment elevation myocardial infarction (STEMI) have worse outcomes and a greater risk of intracranial bleeding than nonelderly patients. Baseline characteristics, clinical outcomes, and the relationship of the tenecteplase (TNK) dose reduction to the efficacy, safety, and electrocardiographic indicators of reperfusion efficacy were evaluated in STEMI patients ≥75 years. METHODS The STREAM trial evaluated early presenting STEMI patients who could not undergo primary percutaneous coronary intervention within 1 hour of first medical contact. Because of excess intracranial hemorrhage (ICH) in patients ≥75 years, the dose of TNK was reduced by 50%. RESULTS Before dose amendment, there were 3 (7.1%) of 42 elderly patients with ICH; 2 of these were fatal, whereas no ICH occurred in the 93 elderly patients who received half-dose TNK postamendment. The median extent of ST-segment elevation resolution (≥50%) and proportion of patients with ≥2 mm in the electrocardiogram lead with greatest ST-segment elevation was comparable in elderly patients preamendment and postamendment (63.2% vs 56.0% and 43.6% vs 40.0%, respectively). Patients requiring rescue coronary intervention after TNK was also similar (42.9% vs 44.1%). The primary composite end point (30-day all-cause death, cardiogenic shock, congestive heart failure, and reinfarction) was 31.0% before versus 24.7% postamendment. CONCLUSIONS Our data, from a modest-sized population of elderly STEMI patients, indicate that half-dose TNK reduces the likelihood of ICH without compromising reperfusion efficacy. These observations are hypothesis generating and warrant further confirmation in randomized clinical trials in the elderly.

Association of metabolic syndrome and its individual components with outcomes among patients with high-risk non–ST-segment elevation acute coronary syndromes

BACKGROUND The relationship of metabolic syndrome and its individual components (obesity, hypertension, glucose intolerance, high triglycerides, and low high-density lipoprotein cholesterol) with 1-year mortality in non-ST-segment elevation acute coronary syndromes (NSTE ACS) patients is not known. METHODS The association of metabolic syndrome (and its individual components) with all-cause mortality within 1 year was assessed in NSTE ACS patients enrolled in the EARLY ACS trial. Adjusted hazard ratio (HR) and 95% CIs are reported. RESULTS Of 9,406 patients, 2,596 (27.6%) had metabolic syndrome. Compared with those without metabolic syndrome, patients with this syndrome were younger, were more often female, and had a higher prevalence of comorbid conditions and higher-risk presenting features. Metabolic syndrome was not associated with increased 1-year mortality (HR 1.20, 95% CI 0.97-1.47; P = .09). The risk of 1-year mortality varied across the individual components: high-density lipoprotein <40 mg/dL (men)/<50 mg/dL (women; or dyslipidemia) was associated with higher risk (HR 1.52, 95% CI 1.15-2.02), and triglycerides >150 mg/dL (or dyslipidemia) was associated with lower risk (HR 0.66, 95% CI 0.54-0.81), whereas the other components (ie, body mass index >30 kg/m(2), fasting plasma glucose >100 mg/dL or diabetes, systolic blood pressure >130 mm Hg or diastolic >85 mm Hg [or hypertension]) were associated with neutral risk of this event. CONCLUSIONS The individual components of metabolic syndrome had varying associations with 1-year mortality, and as an integrated diagnosis, metabolic syndrome was not significantly associated with 1-year mortality. Thus, patient case-mix of the studied NSTE ACS population may influence the observed relationship of metabolic syndrome with subsequent cardiovascular events.

Prognostic implications of quantitative evaluation of baseline Q-wave width in ST-segment elevation myocardial infarction

OBJECTIVES To evaluate quantitative relationships between baseline Q-wave width and 90-day outcomes in ST-segment elevation myocardial infarction (STEMI). BACKGROUND Baseline Q-waves are useful in predicting clinical outcomes after MI. METHODS 3589 STEMI patients were assessed from a multi-centre study. RESULTS 1156 patients of the overall cohort had pathologic Q-waves. The 90-day mortality and the composite of mortality, congestive heart failure (CHF), or cardiogenic shock (p<0.001 for both outcomes) rose as Q-wave width increased. After adapting a threshold ≥40ms for inferior and ≥20ms for lateral/apical MI in all patients (n=3065) with any measureable Q-wave we found hazard ratios (HR) for mortality (HR: 2.44, 95% confidence interval (CI) (1.54-3.85), p<0.001) and the composite (HR: 2.32, 95% CI (1.70-3.16), p<0.001). This improved reclassification of patients experiencing the composite endpoint versus the conventional definition (net reclassification index (NRI): 0.23, 95% CI (0.09-0.36), p<0.001) and universal MI definition (NRI: 0.15, 95% CI (0.02-0.29), p=0.027). CONCLUSIONS The width of the baseline Q-wave in STEMI adds prognostic value in predicting 90-day clinical outcomes. A threshold of ≥40ms in inferior and ≥20ms for lateral/apical MI enhances prognostic insight beyond current criteria.