François Harel

Cardiac Resynchronization Therapy in Patients With Heart Failure and a QRS Complex <120 Milliseconds The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) Trial

Background— Although the benefits of cardiac resynchronization therapy are well established in selected patients with heart failure and a prolonged QRS duration, salutary effects in patients with narrow QRS complexes remain to be demonstrated. Methods and Results— The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial is a randomized, double-blind, 12-center study that was designed to compare the effects of active and inactive cardiac resynchronization therapy in patients with severe left ventricular dysfunction and a QRS duration <120 milliseconds. The trial was interrupted prematurely by the Data Safety and Monitoring Board because of futility and safety concerns after 85 patients were randomized. Changes in exercise duration after 12 months were no different in patients with and without active cardiac resynchronization therapy (−0.7 minutes [95% confidence interval (CI), −2.9 to 1.5] versus 0.8 minutes [95% CI, −1.2 to 2.9]; P=0.31]. Similarly, no significant differences were observed in left ventricular end-systolic volumes (−6.4 mL [95% CI, −18.8 to 5.9] versus 3.1 mL [95% CI, −9.2 to 15.5]; P=0.28) and ejection fraction (3.3% [95% CI, 0.7–6.0] versus 2.1% [95% CI, −0.5 to 4.8]; P=0.52). Moreover, cardiac resynchronization therapy was associated with a significant reduction in the 6-minute walk distance (−11.3 m [95% CI, −31.7 to 9.7] versus 25.3 m [95% CI, 6.1–44.5]; P=0.01), an increase in QRS duration (40.2 milliseconds [95% CI, 34.2–46.2] versus 3.4 milliseconds [95% CI, 0.6–6.2]; P<0.0001), and a nonsignificant trend toward an increase in heart failure–related hospitalizations (15 hospitalizations in 5 patients versus 4 hospitalizations in 4 patients). Conclusions— In patients with a left ventricular ejection fraction ⩽35%, symptoms of heart failure, and a QRS duration <120 milliseconds, cardiac resynchronization therapy did not improve clinical outcomes or left ventricular remodeling and was associated with potential harm. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00900549.Background —While the benefits of cardiac resynchronization therapy (CRT) are well established in selected patients with heart failure and a prolonged QRS duration, salutary effects in patients with narrow QRS complexes remain to be demonstrated. Methods and Results —The LESSER-EARTH trial is a randomized, double-blind, 12-center study that was designed to compare the effects of active versus inactive CRT therapy in patients with severe left ventricular dysfunction and a QRS duration <120 ms. The trial was prematurely interrupted by the Data Safety and Monitoring Board due to futility and safety concerns after 85 patients were randomized. Changes in exercise duration after 12 months were no different in patients with and without active CRT [-0.7 (-2.9, 1.5) minutes versus +0.8 (-1.2, 2.9) minutes, P =0.31]. Similarly, no significant differences were observed in left ventricular end-systolic volumes [-6.4 (-18.8, 5.9) mL versus +3.1 (-9.2, 15.5) mL, P =0.28] and ejection fraction [+3.3% (0.7%, 6.0%) versus +2.1% (-0.5%, 4.8%), P =0.52]. Moreover, CRT was associated with a significant reduction in the 6-minute walk distance [-11.3 (-31.7, 9.7) meters versus +25.3 (6.1, 44.5) meters, P =0.01], an increase in QRS duration [40.2 (34.2, 46.2) ms versus 3.4 (0.6, 6.2) ms, P <0.0001], and a non-significant trend towards an increase in heart failure-related hospitalizations (15 hospitalizations in 5 patients versus 4 hospitalizations in 4 patients). Conclusions —In patients with a left ventricular ejection fraction ≤35%, symptoms of heart failure, and a QRS duration <120 ms, CRT did not improve clinical outcomes or left ventricular remodelling, and was associated with potential harm. Clinical Trial Registration Information —ClinicalTrials.gov. Identifier: [NCT00900549][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00900549&atom=%2Fcirculationaha%2Fearly%2F2013%2F02%2F05%2FCIRCULATIONAHA.112.001239.atom

Left Ventricular Versus Simultaneous Biventricular Pacing in Patients With Heart Failure and a QRS Complex ≥120 Milliseconds

Background— Left ventricular (LV) pacing alone may theoretically avoid deleterious effects of right ventricular pacing. Methods and Results— In a multicenter, double-blind, crossover trial, we compared the effects of LV and biventricular (BiV) pacing on exercise tolerance and LV remodeling in patients with an LV ejection fraction ⩽35%, QRS ≥120 milliseconds, and symptoms of heart failure. A total of 211 patients were recruited from 11 centers. After a run-in period of 2 to 8 weeks, 121 qualifying patients were randomized to LV followed by BiV pacing or vice versa for consecutive 6-month periods. The greatest improvement in New York Heart Association class and 6-minute walk test occurred during the run-in phase before randomization. Exercise duration at 75% of peak VO2 (primary outcome) increased from 9.3±6.4 to 14.0±11.9 and 14.3±12.5 minutes with LV and BiV pacing, respectively, with no difference between groups (P=0.4327). LV ejection fraction improved from 24.4±6.3% to 31.9±10.8% and 30.9±9.8% with LV and BiV pacing, respectively, with no difference between groups (P=0.4530). Reductions in LV end-systolic volume were likewise similar (P=0.6788). The proportion of clinical responders (≥20% increase in exercise duration) to LV and BiV pacing was 48.0% and 55.1% (P=0.1615). Positive remodeling responses (≥15% reduction in LV end-systolic volume) were observed in 46.7% and 55.4% (P=0.0881). Overall, 30.6% of LV nonresponders improved with BiV and 17.1% of BiV nonresponders improved with LV pacing. Conclusion— LV pacing is not superior to BiV pacing. However, nonresponders to BiV pacing may respond favorably to LV pacing, suggesting a potential role as tiered therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00901212.

The hemodynamically unstable patient in the intensive care unit: Hemodynamic vs. transesophageal echocardiographic monitoring

ObjectiveTransesophageal echocardiography is a diagnostic and monitoring modality. The objectives of our study were to compare the diagnoses obtained with continuous transesophageal echocardiography and hemodynamic monitoring in the intensive care unit, to determine interobserver variability of diagnosis obtained with both modalities, and to evaluate its impact. DesignProspective cohort study. SettingSurgical intensive care unit. PatientsConsecutive hemodynamically unstable patients after cardiac surgery. InterventionsAt admission, unstable patients were monitored during 4 hrs with transesophageal echocardiography and standard hemodynamic monitoring. The critical care physician evaluated the patients based on all information except the transesophageal echocardiography at 0, 2, and 4 hrs and formulated a hypothesis on the most likely cause of hemodynamic instability. Transesophageal echocardiography information was provided after each evaluation. To evaluate interobserver variability, all the hemodynamic and echocardiographic information was gathered, randomized, and evaluated by five clinicians for the hemodynamic data and five echocardiographers for the transesophageal echocardiography data. The evaluators were blinded to all other information. Kappa statistics were used to evaluate agreement. Impact of transesophageal echocardiography was assessed retrospectively by using the Deutsch scale. ResultsTwenty patients qualified for the study. The agreement between the hemodynamic and echocardiographic diagnosis showed a kappa at admission, 2 hrs, and 4 hrs of 0.33, 0.47, and 0.28. The interobserver agreement for the initial diagnosis (p = .014) and between all evaluators (p < .001) was significantly higher in the echocardiographic compared with the hemodynamic group. The transesophageal echocardiographic information was considered retrospectively to be essential in 34% and valuable in 34% of cases. ConclusionsThese observations support the belief that transesophageal echocardiographic monitoring in the intensive care unit is associated with higher interobserver agreement in diagnosing and excluding significant causes of hemodynamic instability for postoperative cardiac surgical patients.

Prevention of Restenosis After Angioplasty in Small Coronary Arteries With Probucol

BACKGROUND Restenosis remains the major limitation of coronary angioplasty. Coronary stents have reduced the incidence of restenosis in selected patients with relatively large vessels. No strategies to date have demonstrated a beneficial effect in vessels < 3.0 mm in diameter. We have shown in the MultiVitamins and Probucol (MVP) Trial that probucol, a potent antioxidant, reduces restenosis after balloon angioplasty. The purpose of this study was to determine whether the benefit of probucol therapy is maintained in the subgroup of patients with smaller coronary vessels. METHODS AND RESULTS We studied a subgroup of 189 patients included in the MVP trial who underwent successful balloon angioplasty of at least one coronary segment with a reference diameter < 3.0 mm. One month before angioplasty, patients were randomly assigned to one of four treatments: placebo, probucol (500 mg), multivitamins (beta-carotene 30000 IU, vitamin C 500 mg, and vitamin E 700 IU), or probucol plus multivitamins twice daily. The treatment was maintained until follow-up angiography was performed at 6 months. The mean reference diameter of this study population was 2.49+/-0.34 mm. Lumen loss was 0.12+/-0.34 mm for probucol, 0.25+/-0.43 mm for the combined treatment, 0.35+/-0.56 mm for vitamins, and 0.38+/-0.51 mm for placebo (P=.005 for probucol). Restenosis rates per segment were 20.0% for probucol, 28.6% for the combined treatment, 45.1% for vitamins, and 37.3% for placebo (P=.006 for probucol). CONCLUSIONS Probucol reduces lumen loss and restenosis rate after balloon angioplasty in small coronary arteries.

Prophylactic Tranexamic Acid and ϵ-Aminocaproic Acid for Primary Myocardial Revascularization

Abstract Background . The efficacy of prophylactic ϵ-aminocaproic acid and tranexamic acid to reduce transfusions after primary myocardial revascularization was evaluated in a teaching hospital context. Methods . Patients (n = 134) received either ϵ-aminocaproic acid (15-g bolus + infusion of 1 g/h), high-dose tranexamic acid (10-g bolus + placebo infusion), or normal saline solution in a double-blind fashion. Anticoagulation and conduct of cardiopulmonary bypass were standardized. Results . Tranexamic acid and ϵ-aminocaproic acid produced a significant reduction in postoperative blood loss compared with placebo (median loss, 438 mL, 538 mL, and 700 mL, respectively). Transfusion of red cells was similar in all three groups. Nonetheless, the percentage of patients receiving hemostatic blood products was significantly decreased in the ϵ-aminocaproic acid group compared with the placebo group (20% versus 43%; p = 0.03). Both tranexamic acid and ϵ-aminocaproic acid significantly decreased total exposure to allogeneic blood products compared with placebo ( p = 0.01 and p = 0.05, respectively), and this reduction was clinically important (median exposure, 2, 2, and 7.5 units, respectively). Fibrinolysis was inhibited significantly in both treatment groups. Conclusions . We conclude that either high-dose tranexamic acid or ϵ-aminocaproic acid effectively reduces transfusions in patients undergoing primary, elective myocardial revascularization.

Comparison of nitroglycerin lingual spray and sublingual tablet on time of onset and duration of brachial artery vasodilation in normal subjects

This study compared the rapidity of onset, the magnitude, and the duration of action of 2 short-acting nitroglycerin preparations using high-resolution brachial ultrasound. Both sublingual tablet and lingual spray formulations caused maximal vasodilation at 3 minutes; however, the spray provided faster (at 2 minutes), greater, and more prolonged (15 minutes) vasodilation than the tablet.

Imaging Biomarkers in Atherosclerosis Trials

Atherosclerosis and its thrombotic complications are the leading cause of morbidity and mortality in developed countries, and the burden of atherosclerotic disease is expected to increase even further in the coming decades due to soaring obesity rates that feed the diabetes epidemic. There is, therefore, a clear need for new drugs targeting atherosclerosis to add to our current therapeutic armamentarium. Drug approval currently is based on multicenter, randomized, placebo-controlled trials with long-term follow-up in thousands of patients to demonstrate clear benefits in mortality and cardiovascular events and to allow adequate assessment of safety. Cardiovascular drug development has become a hostage to its own success. New drugs must be compared to placebo but on the background of highly effective standard therapy that lowers event rates and necessitates huge sample sizes and long follow-up. Failures of promising new cardiovascular drugs in large clinical trials1 have had catastrophic consequences for the sponsoring pharmaceutical and biotechnological companies. These conditions are inhibiting new drug development and are stimulating a search for alternate methods to assess new compounds. Cardiovascular imaging techniques have been used to fill this need.2 Cardiovascular imaging trials are shorter and require only a fraction of the patients needed for a large events trial because all patients who complete an imaging trial contribute to the end point. Thus, imaging trials are less expensive. By themselves, they are not sufficient for drug approval by regulatory agencies partly because of the limited safety data that can be generated with the study drug given the number of patients involved and duration of exposure. Nevertheless, imaging studies can provide evidence to inform the decision about whether a large outcome trial should proceed. They are therefore currently best suited in phase 2 of drug development. Ideally, imaging studies also should provide useful data regarding the mechanism …

Near-Infrared Spectroscopy to Monitor Peripheral Blood Flow Perfusion

BackgroundNon-invasive evaluation of peripheral perfusion may be useful in many contexts including peri-operative monitoring. We validated a novel non-invasive spectroscopy technique to assess peripheral perfusion. This method, which is based on the measurement of tissue saturation variations after an ischemic period, was compared to strain gauge plethysmography and radionuclide plethysmography. The technique uses near-infrared spectroscopy (NIRS) to determine the rate of change of forearm tissue saturation during reactive hyperemia.MethodsIn a prospective crossover study, 25 subjects were simultaneously evaluated with NIRS and strain gauge plethysmography. Six baseline flow measurements were performed to assess the reproducibility of each method. Twenty-seven serial measurements were then made to evaluate flow variation during forearm reactive hyperemia.ResultsStrain gauge and NIRS methods showed excellent reproducibility with intra-class correlation coefficients of 0.96 and 0.93, respectively.ConclusionThe NIRS technique appears well suited for the non-invasive evaluation of limb perfusion.

Effects of the tumor necrosis factor-α antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: results of a randomized controlled trial.

Background—Psoriasis is a chronic inflammatory disease associated with increased risks of myocardial infarction and stroke. Systemic treatments for moderate to severe psoriasis can reduce skin and joint inflammation; however, their effects on vascular inflammation are unknown. Methods and Results—This randomized, controlled trial included 30 patients with moderate to severe psoriasis and a history, or multiple risk factors, of coronary atherosclerosis. Patients were randomized (2:1) to receive either adalimumab subcutaneously for 4 months or to control nonsystemic treatment (topical therapies or phototherapy). Vascular inflammation was measured in the carotid artery and ascending aorta at baseline and week 15, by 18F-fluorodeoxyglucose uptake on positron emission tomography. The change in target:background ratio in the vessel with highest baseline target:background ratio (primary end point) was significant at week 15 compared with baseline for patients randomized to adalimumab (–0.23 [95% CI, –0.39 to –0.08]; P=0.004) but not for the control group (–0.10 [95% CI, –0.32 to 0.12]; P=0.35). The difference between study arms for this primary end point did not reach statistical significance (–0.13 [95% CI, –0.01 to 0.14]; P=0.32). The change in target:background ratio at week 15 improved with adalimumab compared with controls both in the ascending aorta (–0.26±0.11, P=0.021) and in carotid arteries (–0.32±0.15, P=0.037) when analyzed separately (secondary end points). Changes in other positron emission tomography indices also improved significantly with adalimumab compared with controls in the ascending aorta and carotids. High-sensitivity C-reactive protein decreased by 51% at week 16 with adalimumab compared with 5% in controls (P=0·002). Conclusions—The study did not meet its primary end point because the change in target:background ratio in patients randomized to adalimumab was not different from controls. Although adalimumab may reduce vascular inflammation in patients with moderate to severe psoriasis, this effect is not large enough to be demonstrated in a study with a small sample size. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NTC00940862.

Effects of the TNF alpha Antagonist Adalimumab on Arterial Inflammation Assessed by Positron Emission Tomography in Patients with Psoriasis: Results of a Randomized Controlled Trial

Background—Psoriasis is a chronic inflammatory disease associated with increased risks of myocardial infarction and stroke. Systemic treatments for moderate to severe psoriasis can reduce skin and joint inflammation; however, their effects on vascular inflammation are unknown. Methods and Results—This randomized, controlled trial included 30 patients with moderate to severe psoriasis and a history, or multiple risk factors, of coronary atherosclerosis. Patients were randomized (2:1) to receive either adalimumab subcutaneously for 4 months or to control nonsystemic treatment (topical therapies or phototherapy). Vascular inflammation was measured in the carotid artery and ascending aorta at baseline and week 15, by 18F-fluorodeoxyglucose uptake on positron emission tomography. The change in target:background ratio in the vessel with highest baseline target:background ratio (primary end point) was significant at week 15 compared with baseline for patients randomized to adalimumab (–0.23 [95% CI, –0.39 to –0.08]; P=0.004) but not for the control group (–0.10 [95% CI, –0.32 to 0.12]; P=0.35). The difference between study arms for this primary end point did not reach statistical significance (–0.13 [95% CI, –0.01 to 0.14]; P=0.32). The change in target:background ratio at week 15 improved with adalimumab compared with controls both in the ascending aorta (–0.26±0.11, P=0.021) and in carotid arteries (–0.32±0.15, P=0.037) when analyzed separately (secondary end points). Changes in other positron emission tomography indices also improved significantly with adalimumab compared with controls in the ascending aorta and carotids. High-sensitivity C-reactive protein decreased by 51% at week 16 with adalimumab compared with 5% in controls (P=0·002). Conclusions—The study did not meet its primary end point because the change in target:background ratio in patients randomized to adalimumab was not different from controls. Although adalimumab may reduce vascular inflammation in patients with moderate to severe psoriasis, this effect is not large enough to be demonstrated in a study with a small sample size. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NTC00940862.