Background
Recent findings suggest that atrial fibrillation is associated with sudden cardiac death (SCD). We examined the incidence, characteristics, and factors associated with SCD in patients with ...atrial fibrillation.
Methods and Results
SCD was defined as witnessed death ≤60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risks models. Over 2.8 years (median), 2349 patients died (40.5 per 1000 patient‐years), of which 1668 (71%) were cardiovascular deaths. SCD was the most common cause of cardiovascular death (n=749; median age 73 years; 70.6% male). Most SCD events occurred out of hospital (92.8%) and without prior symptoms (66.0%). Predictors of SCD included low ejection fraction, heart failure, and prior myocardial infarction (P<0.001 for each). Additional significant baseline predictors of SCD, but not of other causes of death, included male sex, electrocardiographic left ventricular hypertrophy, higher heart rate, nonuse of beta blockers, and use of digitalis. The latter was associated with SCD in patients with or without heart failure (adjusted hazard ratio 1.55 95% CI 1.29–1.86 and 1.56 95% CI 1.14–2.11, respectively; Pinteraction=0.73). The rate of SCD was numerically but not statistically lower with edoxaban (1.20% per year with lower dose edoxaban; 1.28% per year with higher dose edoxaban) compared with warfarin (1.40% per year).
Conclusion
SCD is the most common cause of cardiovascular death in patients with atrial fibrillation and has several distinct predictors, some of which are modifiable. These findings may be considered in planning research and treatment strategies for patients with atrial fibrillation.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.
In the PEGASUS-TIMI 54 trial, treatment with ticagrelor reduced the incidence of cardiovascular death, myocardial infarction, or stroke by 15% to 16% among stable patients compared with placebo. ...However, more patients prematurely discontinued treatment with ticagrelor than with placebo.
To investigate the reasons and timing of discontinuation of treatment with ticagrelor among stable patients prior myocardial infarction.
In the PEGASUS-TIMI 54 trial, 21 162 stable outpatients with prior myocardial infarction were randomly assigned to 90 mg of ticagrelor twice daily, 60 mg of ticagrelor twice daily, or placebo, with all of the patients receiving a low dose of aspirin. These participants were followed up for a median of 33 months (study start date: October 2010; completion date: December 2014). Discontinuation of treatment was evaluated by treatment arm, cause, and timing. This analysis was initiated in May 2015.
Discontinuation of treatment.
Over 33 months, 32%, 29%, and 21% of patients receiving 90 mg of ticagrelor, 60 mg of ticagrelor, and placebo, respectively, discontinued treatment (P < .001). Discontinuation of treatment due to an adverse event occurred in 19%, 16%, and 9% of patients, respectively (P < .001). The most frequent adverse events leading to discontinuation of treatment were bleeding (with Kaplan-Meier event rates of 7.8%, 6.2%, and 1.5% of patients, respectively; P < .001) and dyspnea (6.5%, 4.6%, and 0.8% of patients, respectively; P < .001). Eighty-six percent of bleeding events that led to the discontinuation of treatment with ticagrelor were nonmajor, and 86% of adverse events due to dyspnea that led to discontinuation of treatment with ticagrelor were mild or moderate in severity. The discontinuation rates are annualized for patients who received 90 mg of ticagrelor twice daily (hazard ratio HR, 2.00 95% CI, 1.84-2.16 for the first year; HR, 1.12 95% CI, 1.00-1.26 for the second and third years) and patients who received 60 mg of ticagrelor twice daily (HR, 1.59 95% CI, 1.46-1.73 for the first year; HR, 1.18 95% CI, 1.06-1.32 for the second and third years) compared with patients who received placebo.
When initiated among stable patients with prior myocardial infarction, discontinuation of treatment with ticagrelor was driven primarily by nonserious adverse events occurring primarily early after randomization. For patients completing 1 year of treatment, the subsequent discontinuation rate was low. These data demonstrate how adverse events considered "nonserious" by traditional trial criteria may have an effect on quality of life and, thus, may precipitate the discontinuation of treatments and underscore the need for patient education and counseling on the timing and nature of adverse effects with the aim of improving adherence when appropriate.
clinicaltrials.gov Identifier: NCT01225562.
Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial ...(Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP).
The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and ≥160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury.
The trial comprised 17 160 patients; mean age, 64.0±6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9;
<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (
=0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 (95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group.
In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure.
URL: https://www.
gov; Unique identifier: NCT01730534.
Abstract Objective Patients with diabetes mellitus (DM) presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI) derived enhanced benefit with dual ...antiplatelet therapy (DAPT) with prasugrel vs. clopidogrel. The risk profile and treatment response to DAPT for medically managed ACS patients with DM remains uncertain. Methods The TRILOGY ACS trial compared aspirin + prasugrel vs. aspirin + clopidogrel for up to 30 months in non-ST-segment elevation (NSTE) ACS patients managed medically without revascularization. We compared treatment-related outcomes among 3539 patients with DM vs. 5767 patients without DM. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. Results Patients with vs. without DM were younger, more commonly female, heavier, and more often had revascularization prior to the index ACS event. The frequency of the primary endpoint through 30 months was higher among patients with vs. without DM (24.8% vs. 16.3%), with a higher risk for those patients with DM treated with insulin vs. those treated without insulin (35.3% vs. 19.9%). There was no significant difference in the frequency of the primary endpoint by treatment with prasugrel vs. clopiodgrel in those with or without DM ( P int = 0.82) and with or without insulin treatment among those with DM ( P int = 0.304). Conclusions Among NSTE ACS patients managed medically without revascularization, patients with DM had a higher risk of ischemic events that was amplified among those treated with insulin. There was no differential treatment effect with a more potent DAPT regimen of aspirin + prasugrel vs. aspirin + clopidogrel.
Aims We sought to assess the incidence of and prognostic factors for heart failure (HF) hospitalization among survivors of high-risk acute myocardial infarction (MI). Methods and results We assessed ...the risk of an initial hospitalization for HF in 11 040 stable MI patients (no major non-fatal cardiovascular events or deaths within 45 days of randomization) without a prior history of HF enrolled in the VALIANT trial. Multivariable models were developed to identify independent predictors of HF and HF or cardiovascular death. Of 11 040 stable post-MI patients, 1139 (10.3%) developed HF during the median 25-month follow-up at a rate of ∼3.4% per year. Most patients, 824 (72.3%), did not have a symptomatic recurrent MI between randomization and the onset of HF. The most important predictors of HF were older age, antecedent diabetes, prior MI before index MI, and reduced renal function. HF markedly increased the risk of death HR(hazard ratio) 8.22; 95% CI(confidence interval), 7.49–9.01. Conclusion HF post high risk-MI occurs in a time-dependent fashion and is usually not directly related to re-infarction. Patients who experience HF beyond the acute phase have increased mortality. Long-term survivors of high-risk MI should be followed closely and treated aggressively beyond the acute MI period.
Background
High‐potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high‐potency statins after ...acute coronary syndromes.
Methods and Results
The Stabilization of pLaques usIng Darapladib‐Thrombolysis in Myocardial Infarction (SOLID‐TIMI 52) trial enrolled patients after an acute coronary syndrome in 36 countries between 2009 and 2011. Statin use was strongly encouraged throughout the trial, and statin potency was at the discretion of the treating physician. A high‐potency statin was defined as ≥40 mg atorvastatin, ≥20 mg rosuvastatin, or 80 mg simvastatin daily. Predictors of nonuse of high‐potency statins were examined using logistic regression. Of the patients included (n=12 446), 11 850 (95.2%) were treated with a statin at baseline after acute coronary syndrome (median 14 days), but only 5212 (41.9%) were on a high‐potency statin. Selected patient factors associated with nonuse of high‐potency statins included age ≥75 years (odds ratio 1.39, 95% CI 1.24–1.56), female sex (odds ratio 1.11, 95% CI 1.02–1.22), renal dysfunction (odds ratio 1.17, 95% CI 1.03–1.32), and heart failure during hospital admission (odds ratio 1.43, 95% CI 1.27–1.62). At 3 months after baseline, only 49% of patients had low‐density lipoprotein cholesterol <70 mg/dL. Among the 5490 patients (59%) who were not on a high‐potency statin at 3 months, lower low‐density lipoprotein cholesterol was a predictor of nonuse of a high‐potency statin after a median of 2.3 years (odds ratio 1.15 for 10 mg/dL decrease, 95% CI 1.11–1.19).
Conclusion
Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high‐potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01000727.
The purpose of this study was to assess the relationship between ischemia detected on continuous electrocardiographic (cECG) recording and cardiovascular outcomes after acute coronary syndrome (ACS).
...The small size of prior studies evaluating cECG prevented full evaluation of the risk associated with ischemia across subpopulations and compared with other methods of risk stratification. Ranolazine, a new antianginal agent, reduces ischemic symptoms in patients with chronic angina and after ACS but the anti-ischemic effect, as detected by cECG, is not known.
In all, 6,560 patients hospitalized with non-ST-segment elevation ACS were randomly assigned to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 36) trial. The cECG was performed for 7 days after randomization. Outcomes were followed for a median of 348 days. Clinical events that occurred during cECG recording were excluded from analysis.
A total of 6,355 (97%) patients had cECG recordings evaluable for ischemia analysis. Patients with >or=1 episode of ischemia on cECG (n = 1,271, 20%) were at increased risk of cardiovascular death (7.7% vs. 2.7%, p < 0.001), MI (9.4% vs. 5.0%, p < 0.001), and recurrent ischemia (17.5% vs. 12.3%, p < 0.001). The relationship with cardiovascular death was independent of baseline characteristics or elevated biomarkers (adjusted hazard ratio: 2.46, p < 0.001). Ischemia on cECG was associated with significantly worse outcomes in several subgroups. Ranolazine did not reduce the rate of ischemia detected on cECG (19.9% vs. 21.0%, hazard ratio: 0.93, p = 0.21).
In more than 6,300 patients with ACS, ischemia detected on cECG occurred frequently and was strongly and independently associated with poor cardiovascular outcomes, including cardiovascular death. Continuous ECG monitoring to detect ischemia after ACS may help to identify patients at increased risk. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes MERLIN; NCT00099788).
We investigated whether prior clopidogrel influenced long-term ischaemic and bleeding risks and modified the randomised treatment effect of clopidogrel versus prasugrel among medically managed ...patients with acute coronary syndromes (ACS) treated with dual antiplatelet therapy.
Medically managed patients with ACS in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial were randomised to clopidogrel versus prasugrel (plus aspirin), stratified by prior clopidogrel use. From the analysis population (n=8927), we compared two groups: 'clopidogrel in-hospital (n=6513)' (clopidogrel started ≤72 h of presentation for index ACS event) and 'prior-clopidogrel (n=2414)' (on clopidogrel ≥5 days before index hospitalisation). Treatment-related differences in ischaemic (all-cause death, cardiovascular (CV) death, myocardial infarction (MI), stroke and the composite of CV death/MI/stroke) and bleeding outcomes (severe/life-threatening or moderate bleeding events based on Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria) through 30 months were analysed between patients in the two groups.
Compared with 'clopidogrel in-hospital,' 'prior clopidogrel' patients were younger (median 64 years vs 66 years, p<0.001), more likely to have prior CV events/revascularisation, and had a higher frequency of CV death, MI or stroke through 30 months (20.8% vs 18.2%, p=0.002), with no difference in bleeding events (2.3% vs 3.4%, p=0.50). Randomised treatment effect (prasugrel vs clopidogrel) was similar for ischaemic and bleeding outcomes in both groups (all pinteraction>0.05).
Patients receiving clopidogrel before admission for ACS and subsequently treated only medically are at higher risk for CV events versus those not previously receiving clopidogrel. More potent antiplatelet inhibition with prasugrel versus clopidogrel did not significantly reduce this risk.
NCT00699998.
The elderly constitute an increasing proportion of acute myocardial infarction patients and have disproportionately high mortality and morbidity. Those with heart failure or impaired left ventricular ...left ventricular function after acute myocardial infarction have high complication and mortality rates. Little is known about outcomes with contemporary therapies in these patients.
The Valsartan in Acute Myocardial Infarction Trial (VALIANT) randomized 14,703 patients with heart failure and/or left ventricular ejection fraction <40% to receive captopril, valsartan, or both. Mortality and a composite end point, including cardiovascular mortality, readmission for heart failure, reinfarction, stroke, and resuscitated cardiac arrest, were compared for the age groups of <65 (n=6988), 65 to 74 (n=4555), 75 to 84 (n=2777), and > or =85 (n=383) years. With increasing age, 3-year mortality almost quadrupled (13.4%, 26.3%, 36.0%, and 52.1%, respectively), composite end-point events more than doubled (25.2%, 41.0%, 52.3%, and 66.8%), and hospital admissions for heart failure almost tripled (12.0%, 23.1%, 31.3%, and 35.4%). Outcomes did not differ between the 3 study treatments in any age group. Adverse events associated with captopril and valsartan were more common in the elderly and in patients receiving combination therapy. With increasing age, use of aspirin, beta-blockers, and statins declined, and use of digoxin, calcium-channel blockers, and non-potassium-sparing diuretics increased. On 3-year multivariable analysis, each 10-year age increase was associated with a hazard ratio of 1.49 (95% CI, 1.426 to 1.557; P<0.0001) for mortality and an odds ratio of 1.38 (95% CI, 1.31 to 1.46; P<0.0001) for readmission with heart failure.
Outcomes remained poor in elderly patients with heart failure and/or impaired left ventricular systolic function after acute myocardial infarction, although most received beta-blockers and all received an ACE inhibitor and/or an angiotensin receptor blocker. Better therapies and increased use of aspirin, beta-blockers, and statins are needed in this important and increasing patient group.
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