Pascal Minini

Relation between heart rate variability and training load in middle-distance runners

PURPOSE Monitoring physical performance is of major importance in competitive sports. Indices commonly used, like resting heart rate, VO2max, and hormones, cannot be easily used because of difficulties in routine use, of variations too small to be reliable, or of technical challenges in acquiring the data. METHODS We chose to assess autonomic nervous system activity using heart rate variability in seven middle-distance runners, aged 24.6 +/- 4.8 yr, during their usual training cycle composed of 3 wk of heavy training periods, followed by a relative resting week. The electrocardiogram was recorded overnight twice a week and temporal and frequency indices of heart rate variability, using Fourier and Wavelet transforms, were calculated. Daily training loads and fatigue sensations were estimated with a questionnaire. Similar recordings were performed in a sedentary control group. RESULTS The results demonstrated a significant and progressive decrease in parasympathetic indices of up to -41% (P < 0.05) during the 3 wk of heavy training, followed by a significant increase during the relative resting week of up to +46% (P < 0.05). The indices of sympathetic activity followed the opposite trend, first up to +31% and then -24% (P < 0.05), respectively. The percentage increasing mean nocturnal heart rate variation remained below 12% (P < 0.05). There was no significant variation in the control group. CONCLUSION This study confirmed that heavy training shifted the cardiac autonomic balance toward a predominance of the sympathetic over the parasympathetic drive. When recorded during the night, heart rate variability appeared to be a better tool than resting heart rate to evaluate cumulated physical fatigue, as it magnified the induced changes in autonomic nervous system activity. These results could be of interest for optimizing individual training profiles.

Screening of Obstructive Sleep Apnea Syndrome by Heart Rate Variability Analysis

BACKGROUND Enhanced nocturnal heart rate variability (HRV) has been evoked in sleep-related breathing disorders. However, its capacity to detect obstructive sleep apnea syndrome (OSAS) has not been systematically determined. Thus, we evaluated the discriminant power of HRV parameters in a first group of patients (G1) and validated their discriminant capacity in a second group (G2). METHODS AND RESULTS In G1, 39 of 91 patients (42.8%) were identified as diseased by polysomnography, as were 24 of 52 patients (46%) in G2. Time-domain HRV variables (SD of NN intervals [SDNN], mean of the standard deviations of all NN intervals for all consecutive 5-minute segments of the recording [SDNN index], square root of the mean of the sum of the squares of differences between adjacent normal RR intervals [r-MSSD], and SD of the averages of NN intervals in all 5-minute segments of the recording [SDANN]) were calculated for daytime and nighttime periods, as well as the differences between daytime and nighttime values (Delta[D/N]). Correlations between HRV variables and OSAS status were analyzed in G1 by use of receiver-operating characteristic (ROC) curves and logistic regression analysis. By ROC curve analysis, 7 variables were significantly associated with OSAS. After adjustment for other variables through multiple logistic regression analysis, Delta[D/N]SDNN index and Delta[D/N] r-MSSD remained significant independent predictors of OSAS, with ORs of 8.22 (95% CI, 3.16 to 21.4) and 2.86 (95% CI, 1.21 to 6.75), respectively. The classification and regression tree methodology demonstrated a sensitivity reaching 89.7% (95% CI, 73.7 to 97.7) with Delta[D/N] SDNN index and a specificity of 98.1% (95% CI, 86.4 to 100) with Delta[D/N] SDNN using appropriate thresholds. These thresholds, applied to G2, yielded a sensitivity of 83% using Delta[D/N] SDNN index and a specificity of 96.5% using Delta[D/N] SDNN. CONCLUSIONS Time-domain HRV analysis may represent an accurate and inexpensive screening tool in clinically suspected OSAS patients and may help focus resources on those at the highest risk.

Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control.

Background: A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non–high-density lipoprotein cholesterol, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin. Methods: Data were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking ezetimibe). In a post hoc analysis, the relationship between average on-treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in multivariable analyses. Results: Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7%–52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event, 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63–0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57–0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL-C were observed with achieved non–high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions. Conclusions: In a post hoc analysis from 10 ODYSSEY trials, greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513.

Efficacy of alirocumab in high cardiovascular risk populations with or without heterozygous familial hypercholesterolemia: Pooled analysis of eight ODYSSEY Phase 3 clinical program trials

OBJECTIVES Despite maximally tolerated statin therapy, many patients with high cardiovascular risk, with or without heterozygous familial hypercholesterolemia may require additional low-density lipoprotein cholesterol (LDL-C) reduction. We report pooled alirocumab (ALI) efficacy and safety data from eight Phase 3 trials in 4629 hypercholesterolemia patients, receiving background statin therapy. MATERIAL AND METHODS Studies were pooled by ALI dose and control: ALI 75/150mg every 2weeks (Q2W; dose increased to 150mg Q2W at Week 12 based on Week 8 LDL-C) versus ezetimibe (EZE; Pool 1) or placebo (PBO; Pool 2), and ALI 150mg Q2W versus PBO (Pool 3). RESULTS Mean baseline LDL-C was 109 vs. 105mg/dL (Pool 1), 129 vs. 130mg/dL (Pool 2) and 126 vs. 125mg/dL (Pool 3). ALI 75/150mg Q2W reduced LDL-C by 48.9% (vs. -19.3% EZE) and 48.6% (vs. +4.2% PBO) from baseline to Week 24, and ALI 150mg Q2W reduced LDL-C by 60.4% (vs. +0.5% PBO; all p<0.0001). LDL-C reductions were sustained to Week 104. Risk-based LDL-C goals (<70mg/dL or <100mg/dL) were achieved by 78.0%, 75.2%, and 79.0% (Pool 1-3) of ALI-treated patients (vs. 52.4%, 6.4%, and 8.4%, respectively, for controls) at Week 24. Consistent reductions were observed in apolipoprotein B, non-high-density lipoprotein cholesterol, and lipoprotein (a) (p<0.0001 vs. control). Common adverse events in ALI-treated patients were nasopharyngitis, injection-site reactions, upper respiratory tract infections, and influenza. CONCLUSIONS Alirocumab treatment significantly reduced LDL-C in high cardiovascular risk patients, enabling most to achieve risk-based LDL-C goals.

Bleeding Risk in Patients With Atrial Fibrillation: The AMADEUS Study

OBJECTIVE This study aimed to assess the impact of combination antithrombotic therapy on stroke and bleeding risk compared with anticoagulation therapy only in patients with atrial fibrillation (AF). METHODS Post hoc analysis of 4,576 patients with AF (mean ± SD age, 70.1 ± 9.1 years; men, 66.5%) enrolled in the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) (n = 2,283) or dose-adjusted vitamin K antagonists (VKAs) (international normalized ratio, 2.0-3.0) (n = 2,293). Of these patients, 848 (18.5%) received antiplatelet therapy (aspirin, clopidogrel, ticlopidine, etc) in addition to anticoagulation treatment (combination antithrombotic therapy). RESULTS A total of 572 (15.3% per year) clinically relevant bleeding and 103 (2.6% per year) major bleeding events occurred. Patients receiving combination antithrombotic therapy had a 2.3- to 2.5-fold increased risk of clinically relevant bleeding events and major bleeding events, respectively, compared with those receiving anticoagulation therapy only. Multivariate analyses (hazard ratio, 95% CI) revealed that the risk of clinically relevant bleeding was significantly increased by age 65 to 74 years (1.44, 1.14-1.82) and ≥ 75 years (1.59, 1.24-2.04, P = .001) and by combination antithrombotic therapy (2.47, 2.07-2.96, P < .0001). The same held true for major bleeding events, with analogous figures for age 65 to 74 years (2.26, 1.08-4.71) and ≥ 75 years (4.19, 1.98-8.87, P = .0004) and for combination antithrombotic therapy (2.23, 1.49-3.34, P < .0001). Combination antithrombotic therapy was not associated with a decrease in ischemic stroke risk compared with anticoagulation therapy only (11 [1.4% per year] vs 22 [0.7% per year]; adjusted hazard ratio, 2.01; 95% CI, 0.94-4.30; P = .07). CONCLUSIONS Combination antithrombotic therapy increases the risk of clinically relevant bleeding and major bleeding in patients with AF and does not appear to reduce the risk of stroke.

Maximal Blood Lactate Level Acts as a Major Discriminant Variable in Exercise Testing for Coronary Artery Disease Detection in Men

BACKGROUND The interpretation of exercise stress testing for coronary artery disease detection is affected by the many differences in chosen variables and mathematical methods. We conducted a prospective trial to evaluate a global muscle fatigue parameter--the blood lactate level achieved at maximal exercise--as a method of distinguishing between diseased and nondiseased coronary status. METHODS AND RESULTS We evaluated 236 consecutive male patients without previous myocardial infarction who had been referred for the diagnosis of coronary artery disease. None of the patients had cardiomyopathy, severe cardiac heart failure, or valvular heart disease. Blood lactate concentration at maximal exercise was measured as well as other classic variables. Correlations between variables and coronary status as assessed by coronary arteriography were described using receiver operating characteristic (ROC) curves and logistic regression analysis. The first four most powerful variables (lactate level, maximal power output, exercise duration, and percentage of maximal predicted heart rate), which are directly representative of the global functional capacity, showed values of 0.777, 0.775, 0.760, and 0.740, respectively, by ROC curve analysis. Mean +/- SD blood lactate level at peak exercise reached 7.68 +/- 2.70 mmol/L in the 153 diseased and 10.56 +/- 2.75 mmol/L in the 83 nondiseased patients (P < .0001). After adjustment for other variables, blood lactate level remained a significant predictor of coronary artery disease by logistic regression analysis (adjusted odds ratio, 1.2; confidence interval, 1.04 to 1.4). CONCLUSIONS Global muscle fatigue as assessed by lactate levels in the blood at maximal exercise appears to be a powerful distinguisher of diseased and nondiseased coronary status.

Effect of alirocumab dose increase on Ldl lowering and lipid goal attainment in patients with dyslipidemia

Objectives The objective of this study is to report the dose response in ODYSSEY phase 3 clinical trials of proprotein convertase subtilisin kexin type 9 inhibition with alirocumab in patients not at prespecified lipid goals who received a per-protocol dose increase from 75 every 2 weeks (Q2W) to 150 mg Q2W. Methods Patients (n=2181) receiving statins were enrolled in six phase 3 randomized, double-blind, double-dummy trials (24–104 weeks): alirocumab versus placebo or ezetimibe 10 mg/day. The 75 mg subcutaneous Q2W dose was increased to 150 mg at week 12 if week 8 LDL cholesterol (LDL-C) was greater than or equal to 70 mg/dl (>100 mg/dl in OPTIONS studies for patients without previous coronary heart disease, but with other risk factors). LDL-C percentage reductions from baseline (on-treatment data, n=1291) were compared at week 12 versus week 24. Results Most patients (n=951; 73.7%) with 75 mg Q2W dose plus background statin achieved LDL-C less than 70 or less than 100 mg/dl at week 8. In 340 (26.3%) patients, alirocumab dose was increased to 150 mg Q2W at week 12, and 60.9% of these patients achieved LDL-C goals at week 24, with an additional 14.2% reduction in LDL-C from week 12 to week 24. Adverse event rates were comparable in patients with versus without a dose increase (72.4 vs. 71.8% in placebo-controlled trials; 67.0 vs. 67.6% in ezetimibe-controlled trials). Conclusion Most patients achieved LDL-C goals with alirocumab 75 mg Q2W plus statins. Of those (26.3%) receiving a dose increase, 60.9% achieved LDL-C goals at week 24 with an additional 14.2% reduction in LDL-C.

RELATIONSHIP BETWEEN MAJOR ADVERSE CARDIOVASCULAR EVENTS AND ACHIEVED LOW-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS IN PHASE 3 ODYSSEY TRIALS OF ALIROCUMAB VERSUS CONTROL

Statin and ezetimibe outcome trials suggest a direct relationship between major adverse cardiovascular events (MACE) and LDL-C levels (~55-195 mg/dL). The CTT meta-analysis of statin trials gave a hazard ratio (HR) of 0.78 for MACE per 39 mg/dL LDL-C reduction. We used data from the alirocumab (ALI

RELATIONSHIP BETWEEN PERCENTAGE REDUCTION IN LOW-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS AND MAJOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE AMONG PATIENTS TREATED WITH STATINS +/- ALIROCUMAB OR EZETIMIBE IN THE PHASE 3 ODYSSEY TRIALS

ACC/AHA 2013 guidelines for atherosclerotic cardiovascular disease (ASCVD) recommend use of statins to achieve 30 to ≥50% reduction in LDL-C. We assessed the relationship of additional LDL-C % reduction and ASCVD event rates in patients (most on maximally tolerated statins ± ezetimibe [EZE] at

Reductions in Atherogenic Lipids and Major Cardiovascular EventsClinical Perspective

Background: A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non–high-density lipoprotein cholesterol, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin. Methods: Data were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking ezetimibe). In a post hoc analysis, the relationship between average on-treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in multivariable analyses. Results: Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7%–52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event, 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63–0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57–0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL-C were observed with achieved non–high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions. Conclusions: In a post hoc analysis from 10 ODYSSEY trials, greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513.