Jan H. Cornel

Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure

Background— Decreased renal function has been found to be an independent risk factor for cardiovascular outcomes in patients with chronic heart failure (CHF) with markedly reduced left ventricular ejection fraction (LVEF). The aim of this analysis was to evaluate the prognostic importance of renal function in a broader spectrum of patients with CHF. Methods and Results— The Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of three component trials that enrolled patients with symptomatic CHF, based on use of ACE inhibitors and reduced (≤40%) or preserved LVEF (>40%). Entry baseline creatinine was required to be below 3.0 mg/dL (265 &mgr;mol/L). Routine baseline serum creatinine assessments were done in 2680 North American patients. An analysis of the estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease equation and LVEF on risk of cardiovascular death or hospitalization for heart failure, as well as on all-cause mortality, was conducted on these 2680 patients. The proportion of patients with eGFR <60 mL/min per 1.73 m2 was 36.0%; 42.6% for CHARM-Alternative, 33.0% for CHARM-Added, and 34.7% for CHARM-Preserved. During the median follow-up of 34.4 months (total 6493 person-years), the primary outcome of cardiovascular death or hospital admission for worsening CHF occurred in 950 of 2680 subjects. Both reduced eGFR and lower LVEF were found to be significant independent predictors of worse outcome after adjustment for major confounding baseline clinical characteristics. The risk for cardiovascular death or hospitalization for worsening CHF as well as the risk for all-cause mortality increased significantly below an eGFR of 60 mL/min per 1.73 m2 (adjusted hazard ratio, 1.54 for 45 to 60 mL/min per 1.73 m2 and 1.86 for <45 mL/min per 1.73 m2 for the primary outcome, both P<0.001, and hazard ratio of 1.50, P=0.006, and 1.91, P=0.001, respectively, for all-cause mortality). The prognostic value of eGFR was not significantly different among the three component trials. There was no significant interaction between renal function, the effect of candesartan, and clinical outcome. Conclusions— Impaired renal function is independently associated with heightened risk for death, cardiovascular death, and hospitalization for heart failure in patients with CHF with both preserved as well as reduced LVEF. There was no evidence that the beneficial effect of candesartan was modified by baseline eGFR.

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

BACKGROUND Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS We conducted a randomized, double‐blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin‐1β, involving 10,061 patients with previous myocardial infarction and a high‐sensitivity C‐reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS At 48 months, the median reduction from baseline in the high‐sensitivity C‐reactive protein level was 26 percentage points greater in the group that received the 50‐mg dose of canakinumab, 37 percentage points greater in the 150‐mg group, and 41 percentage points greater in the 300‐mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow‐up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person‐years in the placebo group, 4.11 events per 100 person‐years in the 50‐mg group, 3.86 events per 100 person‐years in the 150‐mg group, and 3.90 events per 100 person‐years in the 300‐mg group. The hazard ratios as compared with placebo were as follows: in the 50‐mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150‐mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300‐mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150‐mg dose, but not the other doses, met the prespecified multiplicity‐adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all‐cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS Antiinflammatory therapy targeting the interleukin‐1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid‐level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.)

Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome

BACKGROUND Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. METHODS We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. RESULTS The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. CONCLUSIONS The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

Lenient versus Strict Rate Control in Patients with Atrial Fibrillation

BACKGROUND Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation. METHODS We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years. RESULTS The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups. CONCLUSIONS In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.)

Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization

BACKGROUND The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes

BACKGROUND Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

Accuracy of currently available techniques for prediction of functional recovery after revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease: comparison of pooled data.

OBJECTIVES This study evaluated the relative merits of the most frequently used techniques for predicting improvement in regional contractile function after coronary revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease. BACKGROUND Several techniques have been proposed for predicting improvement in regional contractile function after revascularization, including thallium-201 (Tl-201) stress-redistribution-reinjection, Tl-201 rest-redistribution, fluorine-18 fluorodeoxyglucose with positron emission tomography, technetium-99m sestamibi imaging and low dose dobutamine echocardiography (LDDE). METHODS A systematic review of all reports on prediction of functional recovery after revascularization in patients with chronic coronary artery disease (published between 1980 and March 1997) revealed 37 with sufficient details for calculating the sensitivity and specificity of each imaging modality. From the pooled data, 95% and 99% confidence intervals were also calculated. RESULTS Sensitivity for predicting regional functional recovery after revascularization was high for all techniques. The specificity of both Tl-201 protocols was significantly lower (p < 0.05) and LDDE significantly higher (p < 0.01) than that of the other techniques. CONCLUSIONS Pooled analysis of 37 studies showed that although all techniques accurately identify segments with improved contractile function after revascularization, the Tl-201 protocols may overestimate functional recovery. The evidence available thus far indicates that LDDE appears to have the highest predictive accuracy.

Prediction of Improvement of Regional Left Ventricular Function After Surgical Revascularization A Comparison of Low-Dose Dobutamine Echocardiography With 201Tl Single-Photon Emission Computed Tomography

BACKGROUND Although both 201Tl scintigraphy and low-dose dobutamine echocardiography (LDDE) have been proposed as effective methods of assessing myocardial viability, their relative efficacies are unknown. The aim of the present study was to compare the two imaging techniques in the prediction of improvement of regional left ventricular (LV) function after surgical revascularization. METHODS AND RESULTS Thirty-eight patients with severe chronic LV dysfunction (ejection fraction < or = 40%, one or more akinetic [Ak] or severely hypokinetic [SH] segments on resting echocardiogram) who underwent uncomplicated coronary artery bypass graft surgery were studied with simultaneous dobutamine stress echocardiography and poststress reinjection 201Tl single-photon emission computed tomography (SPECT) before surgery. The Ak or SH segments were considered viable by LDDE when wall thickening improved during the infusion of 10 micrograms.kg-1 min 1 dobutamine. Scintigraphic definition of viability was the presence of normal 201Tl uptake, totally reversible defect, partially reversible defect, or moderately severe fixed defect. The postoperative improvement of dyssynergic segments was determined with a rest echocardiogram 3 months after surgery. Of 608 LV segments, 169 were classified as Ak and 51 as SH on resting preoperative echocardiography. Of these, 170 were successfully revascularized. Wall motion during LDDE improved in 33 severely dyssynergic segments and was more frequent in SH than in Ak segments (19 of 44 versus 14 of 126, P < .0001). Viability was detected by 201Tl SPECT criteria in 103 SH or Ak segments. Thirty-two of the 33 segments from LDDE responders were judged viable on 201Tl SPECT, whereas 201Tl viability was also detected in 71 of 137 segments from LDDE nonresponders. The sensitivity and the specificity for the prediction of postoperative improvement of segmental wall motion were 74% (95% confidence interval [CI], 67% to 81%) and 95% (95% CI, 92% to 98%) by LDDE and 89% (95% CI, 84% to 94%) and 48% (95% 40% to 56%) by 201Tl SPECT, respectively. Positive predictive value of LDDE was higher than that of 201Tl SPECT (85%, [95% CI, 80% to 90%] versus 33% [95% CI, 26% to 40%]). Thirty-six patients had angina before and only 1 had angina 3 months after revascularization. High-dose dobutamine echocardiography demonstrated significant reduction in stress-induced ischemia (new or worsening of preexisting wall motion abnormalities) after surgery (from 163 to 23 LV segments). CONCLUSIONS In patients with severe chronic LV dysfunction, LDDE is a good predictor of the improvement of dyssynergic segments after revascularization. Because 201Tl SPECT overestimates the probability of postoperative improvement of dyssynergic segments, LDDE should be the preferred imaging technique for preoperative assessment of these patients.

Improvement of left ventricular ejection fraction, heart failure symptoms and prognosis after revascularization in patients with chronic coronary artery disease and viable myocardium detected by dobutamine stress echocardiography

OBJECTIVES This study was designed to address, in patients with severe ischemic left ventricular dysfunction, whether dobutamine stress echocardiography (DSE) can predict improvement of left ventricular ejection fraction (LVEF), functional status and long-term prognosis after revascularization. BACKGROUND Dobutamine stress echocardiography can predict improvement of wall motion after revascularization. The relation between viability, improvement of function, improvement of heart failure symptoms and long-term prognosis has not been studied. METHODS We studied 68 patients with DSE before revascularization; 62 patients underwent resting echocardiography/radionuclide ventriculography before and three months after revascularization. Long-term follow-up data (New York Heart Association [NYHA] functional class, Canadian Cardiovascular Society [CCS] classification and events) were acquired up to two years. RESULTS Patients with > or =4 viable segments on DSE (group A, n = 22) improved in LVEF at three months (from 27+/-6% to 33+/-7%, p < 0.01), in NYHA functional class (from 3.2+/-0.7 to 1.6+/-0.5, p < 0.01) and in CCS classification (from 2.9+/-0.3 to 1.2+/-0.4, p < 0.01); in patients with <4 viable segments (group B, n = 40) LVEF and NYHA functional class did not improve, whereas CCS classification improved significantly (from 3.0+/-0.8 to 1.3+/-0.5, p < 0.01). A higher event rate was observed at long-term follow-up in group B versus group A (47% vs. 17%, p < 0.05). CONCLUSIONS Patients with substantial viability on DSE demonstrated improvement in LVEF and NYHA functional class after revascularization; viability was also associated with a favorable prognosis after revascularization.

Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial

Aims Patients with diabetes mellitus (DM) have high platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronary syndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similar rates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelor vs. clopidogrel in patients with DM or poor glycaemic control. Methods and results We analysed patients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13 951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patients with DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76–1.03), all-cause mortality (HR: 0.82, 95% CI: 0.66–1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36–1.17) with no increase in major bleeding (HR: 0.95, 95% CI: 0.81–1.12) with ticagrelor was consistent with the overall cohort and without significant diabetes status-by-treatment interactions. There was no heterogeneity between patients with or without ongoing insulin treatment. Ticagrelor reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI: 0.70–0.91; HR: 0.78, 95% CI: 0.65–0.93; and HR: 0.62, 95% CI: 0.39–1.00, respectively) with similar bleeding rates (HR: 0.98, 95% CI: 0.86–1.12). Conclusion Ticagrelor, when compared with clopidogrel, reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, without an increase in major bleeding events.