Association of Incident Cardiovascular Disease With Time Course and Cumulative Exposure to Multiple Risk Factors.

BACKGROUND: The quantitative relationship of incident cardiovascular disease (CVD) to lifetime cumulative risk factor exposure is not well understood. OBJECTIVES: Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we examined the quantitative associations of cumulative exposure over time to multiple, simultaneously operating risk factors with CVD incidence and the incidence of its components. METHODS: Regression models were developed quantifying the influence of the time course and severity of multiple CVD risk factors, operating simultaneously, on risk of incident CVD. The outcomes were incident CVD and the incidence of its components: coronary heart disease, stroke, and congestive heart failure. RESULTS: Our study included 4,958 asymptomatic adults enrolled in CARDIA from 1985 to 1986 (ages 18 to 30 years) who were followed for 30 years. Risk of incident CVD depends on the time course and severity of a series of independent risk factors, the impact of which is mediated by their effects on individual CVD components after age 40 years. Cumulative exposure (AUC vs time) to low-density lipoprotein cholesterol and triglycerides was independently associated with risk of incident CVD. Of the blood pressure variables, areas under the mean arterial pressure vs time curve and the pulse pressure vs time curve were strongly and independently associated with incident CVD risk. CONCLUSIONS: The quantitative description of the link between risk factors and CVD informs the construction of individualized CVD mitigation strategies, design of primary prevention trials, and assessment of public health impact of risk factor-based interventions.

Association of Cumulative Systolic Blood Pressure With Long-Term Risk of Cardiovascular Disease and Healthy Longevity: Findings From the Lifetime Risk Pooling Project Cohorts.

Hypertension is a major risk factor for cardiovascular disease (CVD), but previous studies have mostly been limited to a single exam, a single cohort, a short follow-up period, or a limited number of outcomes. This study aimed to assess the association of 10-year cumulative systolic blood pressure (BP) in middle age with long-term risk of any CVD, coronary heart disease, stroke, heart failure, all-cause mortality, and healthy longevity. Individuals (11 502) from 5 racially/ethnically diverse US community-based cohorts were included in this study once they met all the inclusion criteria: ≥10 year of observation in the included cohort, aged 45 to 60 years, free of CVD, and had ≥3 visits with BP exams over the preceding 10 years. For each participant, systolic BP level was predicted for each year of the 10-year prior inclusion, based on the available exams (median of 4.0; spread over, 9.1 [range, 7.2-10] years). Lower 10-year cumulative systolic BP was associated with 4.1 years longer survival and 5.4 years later onset of CVD, resulting in living longer life with a shorter period with morbidity. Models adjusted for sociodemographic characteristics, cardiovascular risk factors, and index systolic BP demonstrated associations of 10-year cumulative systolic BP (per 130 mm Hg×year change, the threshold for stage-1 hypertension) with CVD (hazard ratio [HR], 1.28 [95% CI, 1.20-1.36]), coronary heart disease (HR, 1.29 [95% CI, 1.19-1.40]), stroke (HR, 1.33 [95% CI, 1.20-1.47]), heart failure (HR, 1.12 [95% CI, 1.02-1.23]), and all-cause mortality (HR, 1.21 [95% CI, 1.14-1.29]). These findings emphasize the importance of 10-year cumulative systolic BP as a risk factor to CVD, above and beyond current systolic BP.

Time Course of LDL Cholesterol Exposure and Cardiovascular Disease Event Risk.

BACKGROUND: Incident cardiovascular disease (CVD) increases with increasing low-density lipoprotein cholesterol (LDL-C) concentration and exposure duration. Area under the LDL-C versus age curve is a possible risk parameter. Data-based demonstration of this metric is unavailable and whether the time course of area accumulation modulates risk is unknown. OBJECTIVES: Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we assessed the relationship of area under LDL-C versus age curve to incident CVD event risk and modulation of risk by time course of area accumulation-whether risk increase for the same area increment is different at different ages. METHODS: This prospective study included 4,958 asymptomatic adults age 18 to 30 years enrolled from 1985 to 1986. The outcome was a composite of nonfatal coronary heart disease, stroke, transient ischemic attack, heart failure hospitalization, cardiac revascularization, peripheral arterial disease intervention, or cardiovascular death. RESULTS: During a median 16-year follow-up after age 40 years, 275 participants had an incident CVD event. After adjustment for sex, race, and traditional risk factors, both area under LDL-C versus age curve and time course of area accumulation (slope of LDL-C curve) were significantly associated with CVD event risk (hazard ratio: 1.053; p < 0.0001 per 100 mg/dl × years; hazard ratio: 0.797 per mg/dl/year; p = 0.045, respectively). CONCLUSIONS: Incident CVD event risk depends on cumulative prior exposure to LDL-C and, independently, time course of area accumulation. The same area accumulated at a younger age, compared with older age, resulted in a greater risk increase, emphasizing the importance of optimal LDL-C control starting early in life.

Long-Term Survival Following Multivessel Revascularization in Patients With Diabetes: The FREEDOM Follow-On Study.

BACKGROUND: The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that for patients with diabetes mellitus (DM) and multivessel coronary disease (MVD), coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention with drug-eluting stents (PCI-DES) in reducing the rate of major adverse cardiovascular and cerebrovascular events after a median follow-up of 3.8 years. It is not known, however, whether CABG confers a survival benefit after an extended follow-up period. OBJECTIVES: The purpose of this study was to evaluate the long-term survival of DM patients with MVD undergoing coronary revascularization in the FREEDOM trial. METHODS: The FREEDOM trial randomized 1,900 patients with DM and MVD to undergo either PCI with sirolimus-eluting or paclitaxel-eluting stents or CABG on a background of optimal medical therapy. After completion of the trial, enrolling centers and patients were invited to participate in the FREEDOM Follow-On study. Survival was evaluated using Kaplan-Meier analysis, and Cox proportional hazards models were used for subgroup and multivariate analyses. RESULTS: A total of 25 centers (of 140 original centers) agreed to participate in the FREEDOM Follow-On study and contributed a total of 943 patients (49.6% of the original cohort) with a median follow-up of 7.5 years (range 0 to 13.2 years). Of the 1,900 patients, there were 314 deaths during the entire follow-up period (204 deaths in the original trial and 110 deaths in the FREEDOM Follow-On). The all-cause mortality rate was significantly higher in the PCI-DES group than in the CABG group (24.3% [159 deaths] vs. 18.3% [112 deaths]; hazard ratio: 1.36; 95% confidence interval: 1.07 to 1.74; p = 0.01). Of the 943 patients with extended follow-up, the all-cause mortality rate was 23.7% (99 deaths) in the PCI-DES group and 18.7% (72 deaths) in the CABG group (hazard ratio: 1.32; 95% confidence interval: 0.97 to 1.78; p = 0.076). CONCLUSIONS: In patients with DM and MVD, coronary revascularization with CABG leads to lower all-cause mortality than with PCI-DES in long-term follow-up. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450).

SYNTAX Score in Patients With Diabetes Undergoing Coronary Revascularization in the FREEDOM Trial.

BACKGROUND: Diabetes mellitus (DM) is associated with complex coronary artery disease (CAD), which in turn results in increased morbidity and mortality from cardiovascular disease. OBJECTIVES: This study sought to evaluate the utility of SYNTAX score (SS) for predicting future cardiovascular events in patients with DM and complex CAD undergoing either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). METHODS: The FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial randomized patients with DM and multivessel CAD to undergo either PCI with drug-eluting stents or CABG. The SS was calculated retrospectively by a core laboratory. The endpoint of hard cardiovascular events (HCE) was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke, while the endpoint of major adverse cardiac and cerebrovascular events (MACCE) was a composite of HCE and repeat revascularization. RESULTS: A total of 1,900 patients were randomized to PCI (n = 953) or CABG (n = 947). The SS was considered an independent predictor of 5-year MACCE (hazard ratio per unit of SS: 1.02; 95% confidence interval: 1.00 to 1.03; p = 0.014) and HCE (hazard ratio per unit of SS: 1.03; 95% confidence interval: 1.01 to 1.04; p = 0.002) in the PCI cohort, but not in the CABG group. There was a higher incidence of MACCE in PCI patients with low, intermediate, and high SS compared with those who underwent CABG (36.6% vs. 25.9%, p = 0.02; 43.9% vs. 26.8%, p < 0.001; 48.7% vs. 29.7%, p = 0.003, respectively). CONCLUSIONS: In DM patients with multivessel CAD, the complexity of CAD evaluated by the SS is an independent risk factor for MACCE and HCE only in patients undergoing PCI. The SS should not be utilized to guide the choice of coronary revascularization in patients with DM and multivessel CAD. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450).

Stroke Rates Following Surgical Versus Percutaneous Coronary Revascularization.

BACKGROUND: Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are used for coronary revascularization in patients with multivessel and left main coronary artery disease. Stroke is among the most feared complications of revascularization. Due to its infrequency, studies with large numbers of patients are required to detect differences in stroke rates between CABG and PCI. OBJECTIVES: This study sought to compare rates of stroke after CABG and PCI and the impact of procedural stroke on long-term mortality. METHODS: We performed a collaborative individual patient-data pooled analysis of 11 randomized clinical trials comparing CABG with PCI using stents; ERACI II (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Patients With Multiple Vessel Disease) (n = 450), ARTS (Arterial Revascularization Therapy Study) (n = 1,205), MASS II (Medicine, Angioplasty, or Surgery Study) (n = 408), SoS (Stent or Surgery) trial (n = 988), SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial (n = 1,800), PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) trial (n = 600), FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial (n = 1,900), VA CARDS (Coronary Artery Revascularization in Diabetes) (n = 198), BEST (Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease) (n = 880), NOBLE (Percutaneous Coronary Angioplasty Versus Coronary Artery Bypass Grafting in Treatment of Unprotected Left Main Stenosis) trial (n = 1,184), and EXCEL (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial (n = 1,905). The 30-day and 5-year stroke rates were compared between CABG and PCI using a random effects Cox proportional hazards model, stratified by trial. The impact of stroke on 5-year mortality was explored. RESULTS: The analysis included 11,518 patients randomly assigned to PCI (n = 5,753) or CABG (n = 5,765) with a mean follow-up of 3.8 ± 1.4 years during which a total of 293 strokes occurred. At 30 days, the rate of stroke was 0.4% after PCI and 1.1% after CABG (hazard ratio [HR]: 0.33; 95% confidence interval [CI]: 0.20 to 0.53; p < 0.001). At 5-year follow-up, stroke remained significantly lower after PCI than after CABG (2.6% vs. 3.2%; HR: 0.77; 95% CI: 0.61 to 0.97; p = 0.027). Rates of stroke between 31 days and 5 years were comparable: 2.2% after PCI versus 2.1% after CABG (HR: 1.05; 95% CI: 0.80 to 1.38; p = 0.72). No significant interactions between treatment and baseline clinical or angiographic variables for the 5-year rate of stroke were present, except for diabetic patients (PCI: 2.6% vs. CABG: 4.9%) and nondiabetic patients (PCI: 2.6% vs. CABG: 2.4%) (p for interaction = 0.004). Patients who experienced a stroke within 30 days of the procedure had significantly higher 5-year mortality versus those without a stroke, both after PCI (45.7% vs. 11.1%, p < 0.001) and CABG (41.5% vs. 8.9%, p < 0.001). CONCLUSIONS: This individual patient-data pooled analysis demonstrates that 5-year stroke rates are significantly lower after PCI compared with CABG, driven by a reduced risk of stroke in the 30-day post-procedural period but a similar risk of stroke between 31 days and 5 years. The greater risk of stroke after CABG compared with PCI was confined to patients with multivessel disease and diabetes. Five-year mortality was markedly higher for patients experiencing a stroke within 30 days after revascularization.

2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data.

BACKGROUND: Numerous randomised trials have compared coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) for patients with coronary artery disease. However, no studies have been powered to detect a difference in mortality between the revascularisation strategies. METHODS: We did a systematic review up to July 19, 2017, to identify randomised clinical trials comparing CABG with PCI using stents. Eligible studies included patients with multivessel or left main coronary artery disease who did not present with acute myocardial infarction, did PCI with stents (bare-metal or drug-eluting), and had more than 1 year of follow-up for all-cause mortality. In a collaborative, pooled analysis of individual patient data from the identified trials, we estimated all-cause mortality up to 5 years using Kaplan-Meier analyses and compared PCI with CABG using a random-effects Cox proportional-hazards model stratified by trial. Consistency of treatment effect was explored in subgroup analyses, with subgroups defined according to baseline clinical and anatomical characteristics. FINDINGS: We included 11 randomised trials involving 11 518 patients selected by heart teams who were assigned to PCI (n=5753) or to CABG (n=5765). 976 patients died over a mean follow-up of 3·8 years (SD 1·4). Mean Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score was 26·0 (SD 9·5), with 1798 (22·1%) of 8138 patients having a SYNTAX score of 33 or higher. 5 year all-cause mortality was 11·2% after PCI and 9·2% after CABG (hazard ratio [HR] 1·20, 95% CI 1·06-1·37; p=0·0038). 5 year all-cause mortality was significantly different between the interventions in patients with multivessel disease (11·5% after PCI vs 8·9% after CABG; HR 1·28, 95% CI 1·09-1·49; p=0·0019), including in those with diabetes (15·5% vs 10·0%; 1·48, 1·19-1·84; p=0·0004), but not in those without diabetes (8·7% vs 8·0%; 1·08, 0·86-1·36; p=0·49). SYNTAX score had a significant effect on the difference between the interventions in multivessel disease. 5 year all-cause mortality was similar between the interventions in patients with left main disease (10·7% after PCI vs 10·5% after CABG; 1·07, 0·87-1·33; p=0·52), regardless of diabetes status and SYNTAX score. INTERPRETATION: CABG had a mortality benefit over PCI in patients with multivessel disease, particularly those with diabetes and higher coronary complexity. No benefit for CABG over PCI was seen in patients with left main disease. Longer follow-up is needed to better define mortality differences between the revascularisation strategies. FUNDING: None.

2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

Associations Between Short or Long Length of Stay and 30-Day Readmission and Mortality in Hospitalized Patients With Heart Failure.

OBJECTIVES: This study sought to examine the associations between heart failure (HF)-related hospital length of stay and 30-day readmissions and HF hospital length of stay and mortality rates. BACKGROUND: Although reducing HF readmission and mortality rates are health care priorities, how HF-related hospital length of stay affects these outcomes is not fully known. METHODS: A population-level, multicenter cohort study of 58,230 patients with HF (age >65 years) was conducted in Ontario, Canada between April 1, 2003 and March 31, 2012. RESULTS: When length of stay was modeled as continuous variable, its association with the rate of cardiovascular readmission was nonlinear (p < 0.001 for nonlinearity) and U-shaped. When analyzed as a categorical variable, there was a higher rate of cardiovascular readmission for short (1 to 2 days; adjusted hazard ratio [HR]: 1.12; 95% confidence interval [CI]: 1.04 to 1.21; p = 0.003) and long (9 to 14 days; HR: 1.11; 95% CI: 1.04 to 1.19; p = 0.002) lengths of stay as compared with 5 to 6 days (reference). Hospital readmissions for HF demonstrated a similar nonlinear (p = 0.005 for nonlinearity) U-shaped relationship with increased rates for short (HR: 1.15; 95% CI: 1.04 to 1.27; p = 0.006) and long (HR: 1.14; 95% CI: 1.04 to 1.25; p = 0.004) lengths of stay. Noncardiovascular readmissions demonstrated increased rates with long (HR: 1.17; 95% CI: 1.07 to 1.29; p < 0.001) and decreased rates with short (HR: 0.87; 95% CI: 0.79 to 0.96; p = 0.006) lengths of stay (p = 0.53 for nonlinearity). The 30-day mortality risk was highest after a long length of stay (HR: 1.28; 95% CI: 1.14 to 1.43; p < 0.001). CONCLUSIONS: A short length of stay after hospitalization for HF is associated with increased rates of cardiovascular and HF readmissions but lower rates of noncardiovascular readmissions. A long length of stay is associated with increased rates of all types of readmission and mortality.

Relation of Post-Coronary Artery Bypass Graft Creatine Kinase-MB Elevations and New Q Waves With Long-Term Cardiovascular Death in Patients With Diabetes Mellitus and Multivessel Coronary Artery Disease.

Associations of early creatine phosphokinase-MB (CK-MB) elevation and new Q waves and their association with cardiovascular death (CVD) after coronary artery bypass grafting (CABG) have been reported, but this association has not been studied in a large population of patients with diabetes mellitus. In this study, we examine the association of periprocedural CK-MB elevations and new Q waves with CVD in the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease trial. Cox proportional hazards regression was used to assess the relation of CK-MB elevations and new Q waves in the first 24 hours after procedure and their relation to CVD; logistic regression was used to assess odds ratios of these variables. Hazard ratios, 95% confidence intervals, and p values associated with Wald chi-square test are reported. CK-MB elevation in first 24 hours after procedure was independently associated with CVD. CVD hazard increased by 6% (p <0.001) with each multiple of CK-MB above the upper reference limit (URL); odds of new post-CABG Q waves increased by a factor of 1.08 (p <0.001); at 7× CK-MB URL, HR was >2. CK-MB URL multiples of 7, 12, and 15 were associated with new Q-wave odds ratios of 9, 16, and 27 times, respectively (p ≤0.001, C-statistic >0.70). New Q waves were independently associated with survival in the multivariate model only when CK-MB was excluded (p = 0.01). In conclusion, independent associations included (1) CVD and early post-CABG CK-MB elevation; (2) new Q waves with early post-CABG CK-MB elevation; (3) CVD with new Q waves only when CK-MB elevation is excluded from analysis.

Next Steps in Primary Prevention of Coronary Heart Disease: Rationale for and Design of the ECAD Trial.

Atherosclerotic cardiovascular disease (ASCVD) events, including coronary heart disease and stroke, are the most frequent cause of death and major disability in the world. Current American College of Cardiology/American Heart Association primary prevention guidelines are mainly on the basis of randomized controlled trials of statin-based low-density lipoprotein cholesterol (LDL-C)-lowering therapy for primary prevention of ASCVD events. Despite the clear demonstration of statin-based LDL-C lowering, substantial 10-year and lifetime risks of incident ASCVD continue. Although the 10-year risk is low in young and middle-aged adults who would not be treated according to current guidelines, they ultimately account for most incident ASCVD. If statin-based LDL-C lowering were initiated in them at an age before complex coronary plaques are common in the population, a substantial reduction in lifetime risk of incident coronary heart disease might be achieved. We examine this hypothesis and introduce the design of a currently recruiting trial to address it. (Eliminate Coronary Artery Disease [ECAD]; NCT02245087).