Michael Shechter

Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction

Background— Although clopidogrel reduces the risk of cardiovascular episodes after coronary events and stenting, a substantial number of incidents continue to occur. Methods and Results— The antiplatelet effect of clopidogrel was studied prospectively in 60 consecutive patients who underwent primary angioplasty (percutaneous coronary intervention [PCI]) with stenting for acute ST-segment–elevation myocardial infarction (STEMI) to determine whether variability in response to clopidogrel affects clinical outcomes. Patients were stratified into 4 quartiles according to the percentage reduction of ADP-induced platelet aggregation. Although patients in the first quartile were resistant to the effects of clopidogrel (ADP-induced platelet aggregation at day 6, 103±8% of baseline), ADP-induced aggregation was reduced to 69±3%, 58±7%, and 33±12% of baseline, respectively, in patients in quartiles 2 through 4 (P <0.01 for all). In addition, epinephrine-induced platelet aggregation and platelet aggregation under flow conditions, assessed by the cone-and-plate(let) analyzer method, were reduced significantly less in the first quartile than in quartiles 2 through 4. Whereas 40% of patients in the first quartile sustained a recurrent cardiovascular event during a 6-month follow-up, only 1 patient (6.7%) in the second quartile and none in the third and fourth quartiles suffered a cardiovascular event (P =0.007). Conclusions— Up to 25% of STEMI patients undergoing primary PCI with stenting are resistant to clopidogrel and therefore may be at increased risk for recurrent cardiovascular events.

Oral Magnesium Therapy Improves Endothelial Function in Patients With Coronary Artery Disease

BackgroundMagnesium blocks many of the physiological actions of calcium. Nevertheless, the impact of magnesium supplementation on endothelial function and exercise tolerance in stable coronary artery disease (CAD) patients has not been assessed. Methods and ResultsIn a randomized, double-blind, placebo-controlled trial, 50 stable CAD patients (41 men and 9 women, mean±SD age 67±11 years, age range 42 to 82 years) were randomized to receive either magnesium (n=25) (30 mmol/d Magnosolv-Granulat; Asta Medica Company, Inc) or placebo (n=25) for 6 months. Before and after 6 months, endothelium-dependent brachial artery flow-mediated vasodilation (FMD) and endothelium-independent NTG-mediated vasodilation were assessed with high-resolution (10-MHz) ultrasound. Exercise stress testing was performed with use of the Bruce protocol. Intracellular magnesium concentrations ([Mg2+]i) were assessed from sublingual cells through x-ray dispersion (EXA) (normal mean±SD values 37.9±4.0 mEq/L). The magnesium therapy significantly increased postintervention ([Mg2+]i versus placebo (36.2±5.0 versus 32.7±2.7 mEq/L, P <0.02). There was a significant correlation in the total population between baseline [Mg2+]i and baseline FMD (r =0.48, P <0.01). The magnesium intervention resulted in a significant improvement in postintervention FMD (15.5±12.0%, P =0.02 compared with baseline), which was not evident with placebo (4.4±2.5%, P =0.78 compared with baseline). There was better exercise tolerance (9.3±2.0 versus 7.3±3.1 minutes, P =0.05) and less ischemic ST-segment changes (4 versus 10 patients, P =0.05) in the magnesium versus placebo groups, respectively. ConclusionsOral magnesium therapy in CAD patients is associated with significant improvement in brachial artery endothelial function and exercise tolerance, suggesting a potential mechanism by which magnesium could beneficially alter outcomes in CAD patients.

Review of echocardiographically diagnosed right heart entrapment of pulmonary emboli-in-transit with emphasis on management

2DE permits detection of thromboemboli transiently entrapped in the right heart chambers while en route to the pulmonary arteries. Review of the 49 cases recorded to date reveals that the supple elongated clot produces a 2DE picture--a mass of changing configuration and striking mobility--that is highly characteristic. Since emboli that become entrapped are large, when managed by medical measures alone they have an attendant mortality rate of 50%, usually soon after 2DE diagnosis, upon completion of pulmonary embolization. Death occurred in 8 of 16 patients treated with anticoagulants, thrombolytic agents, or antiaggregants and in 6 of 13 who received supportive measures only. Of 20 patients referred for surgery (cardiotomy and, in 17, pulmonary embolectomy), only three died, two of them failures of preceding anticoagulant treatment. These data indicate that thromboemboli entrapped in the right heart chambers are best handled as a surgical emergency.

Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (RIVER-PCI): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Incomplete revascularisation is common after percutaneous coronary intervention and is associated with increased mortality and adverse cardiovascular events. We aimed to assess whether adjunctive anti-ischaemic pharmacotherapy with ranolazine would improve the prognosis of patients with incomplete revascularisation after percutaneous coronary intervention. METHODS We performed this multicentre, randomised, parallel-group, double-blind, placebo-controlled, event-driven trial at 245 centres in 15 countries in Europe, Israel, Russia, and the USA. Patients (aged ≥18 years) with a history of chronic angina with incomplete revascularisation after percutaneous coronary intervention (defined as one or more lesions with ≥50% diameter stenosis in a coronary artery ≥2 mm diameter) were randomly assigned (1:1), via an interactive web-based block randomisation system (block sizes of ten), to receive either twice-daily oral ranolazine 1000 mg or matching placebo. Randomisation was stratified by diabetes history (presence vs absence) and acute coronary syndrome presentation (acute coronary syndrome vs non-acute coronary syndrome). Study investigators, including all research teams, and patients were masked to treatment allocation. The primary endpoint was time to first occurrence of ischaemia-driven revascularisation or ischaemia-driven hospitalisation without revascularisation. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT01442038. FINDINGS Between Nov 3, 2011, and May 27, 2013, we randomly assigned 2651 patients to receive ranolazine (n=1332) or placebo (n=1319); 2604 (98%) patients comprised the full analysis set. After a median follow-up of 643 days (IQR 575-758), the composite primary endpoint occurred in 345 (26%) patients assigned to ranolazine and 364 (28%) patients assigned to placebo (hazard ratio 0·95, 95% CI 0·82-1·10; p=0·48). Incidence of ischaemia-driven revascularisation and ischaemia-driven hospitalisation did not differ significantly between groups. 189 (14%) patients in the ranolazine group and 137 (11%) patients in the placebo group discontinued study drug because of an adverse event (p=0·04). INTERPRETATION Ranolazine did not reduce the composite rate of ischaemia-driven revascularisation or hospitalisation without revascularisation in patients with a history of chronic angina who had incomplete revascularisation after percutaneous coronary intervention. Further studies are warranted to establish whether other treatment could be effective in improving the prognosis of high-risk patients in this population. FUNDING Gilead Sciences, Menarini.

Increased mean platelet volume is associated with non-responsiveness to clopidogrel

Prior studies have demonstrated significant individual variability of platelet response to clopidogrel, which affects clinical outcome. In patients with stable coronary artery disease (CAD) smoking, diabetes mellitus, elevated body mass index and renal insufficiency, significantly impact response to clopidogrel. The determinants of platelet response to clopidogrel in patients with acute coronary syndrome are unknown. Adenosine diphosphate (ADP)-induced platelet aggregation (PA), hs C-reactive protein, platelet count and mean platelet volume (MPV) were determined 72 hours post clopidogrel loading in 276 consecutive acute myocardial infarction (AMI) patients. Patients with ADP-platelet aggregation ≥ 70% were considered to be clopidogrel non-responders. Eighty-four patients (30%) were clopidogrel non-responders and 192 (70%) were responders (ADP-induced PA: 81 ± 17% vs 49 ± 17%, respectively, p<0.001). Both study groups were comparable with respect to age, gender, prior cardiovascular history, prior aspirin use and risk factors for CAD, including smoking (42% for both groups) and diabetes mellitus (26% vs 22%, respectively, p=0.4). Responders and non-responders had similar angiographic characteristics, indices of infarct size, and similar hs-CRP (29 ± 34 vs 28 ± 34 mg/l, p=0.7) and creatinine (1.08 ± 0.4 mg% vs 1.07 ± 0.4, p=0.9) levels. On the contrary non-responders had significantly larger mean MPV (9 ± 1.2 fl vs 8 ± 1 fl, respectively, p=0.0018), and when patients were stratified into quartiles based on MPV, ADP-induced PA increased gradually and significantly across the quartiles of MPV (p<0.001). In conclusion, increased MPV associated with platelet activation, predicts non-responsiveness to clopidogrel among patients with acute coronary syndrome.

Frequency and prognostic significance of secondary ventricular fibrillation complicating acute myocardial infarction

The incidence of secondary ventricular fibrillation (VF) complicating acute myocardial infarction (AMI) was 2.4% in a large cohort of unselected patients with AMI (142 of 5,839). Secondary VF was more frequent in patients with recurrent AMI (4%) than in those with a first AMI (1.9%) (p < 0.01). The hospital course was more complicated and in-hospital mortality was significantly higher in patients with secondary VF than in those with the same clinical hemodynamic condition but without VF (56 vs 16%; p < 0.0001). Multivariate analyses confirmed secondary VF complicating AMI as an independent predictor of high in-hospital mortality, with an odds ratio of 7 (95% confidence interval 4.6-10.6). However, long-term mortality after discharge (mean follow-up 5.5 years) was not increased in patients with as compared with those without secondary VF (39 vs 42%). These findings were also true when patients receiving beta blockers and antiarrhythmic therapy were excluded from analysis. Thus, this life-threatening arrhythmia occurring during hospitalization is not a marker of recurrent susceptibility to VF or an indicator of increased mortality after discharge from the hospital.

Reduction in Life-Threatening Ventricular Tachyarrhythmias in Statin-Treated Patients With Nonischemic Cardiomyopathy Enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy)

OBJECTIVES This study hypothesized that time-dependent statin therapy will reduce the risk of life-threatening ventricular tachyarrhythmias among patients with nonischemic cardiomyopathy (NICM) enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). BACKGROUND Prior studies suggested that statin therapy exerts antiarrhythmic properties among patients with coronary artery disease. However, data regarding the effect of statins on arrhythmic risk among patients with NICM are limited. METHODS Multivariate Cox proportional hazards regression modeling was used to assess the effect of statin therapy, evaluated as a time-dependent covariate, on the risk of appropriate defibrillator therapy for fast ventricular tachycardia (VT) (defined as a rate faster than 180 beats/min)/ventricular fibrillation (VF) or death (primary endpoint) and appropriate defibrillator shocks (secondary endpoint) among 821 patients with NICM enrolled in the MADIT-CRT trial. RESULTS Statin users (n = 499) were older and had a higher prevalence of diabetes and hypertension yet were less frequently smokers. Multivariate analysis showed that time-dependent statin therapy was independently associated with a significant 77% reduction in the risk of fast VT/VF or death (p < 0.001) and with a significant 46% reduction in the risk of appropriate implantable cardioverter defibrillator shocks (p = 0.01). Consistent with these findings, the cumulative probability of fast VT/VF or death at 4 years of follow-up was significantly lower among patients who were treated with statins (11%) as compared with study patients who were not treated with statins (19%; p = 0.006 for the overall difference during follow-up). CONCLUSIONS Statin use was associated with a significant reduction in the risk of life-threatening ventricular tachyarrhythmias among patients with NICM.

Statins have an early antiplatelet effect in patients with acute myocardial infarction

Statins confer an antiplatelet effect in hypercholesterolemic subjects and in stable coronary artery disease patients. We explored the antiplatelet effects of statins in ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty. Of 120 STEMI patients, 80 (67%) received statins while 40 (33%) did not. Ex vivo platelet reactivity was studied on admission and 72 hours later by conventional aggregometry and under flow conditions (Impact R). Measures of platelet reactivity under flow conditions included aggregate size and surface coverage, signifying platelet aggregation and adhesion respectively. The effect of statins on platelet function under flow conditions and platelet aggregation was studied in vitro in platelets from 10 STEMI patients. Platelets from each patient were incubated in vitro with lovastatin or PBS as a control. The effect of lovastatin in the presence of a nitric oxide synthase inhibitor (L-NMMA) was also studied. Patients treated with statins were compared with those who did not have significantly lower ADP-induced platelet aggregation on the 4th day (56 ± 18% vs. 64 ± 17%, p = 0.02). Platelet deposition under flow conditions as measured by surface coverage was reduced from admission to 72 hours later among statin-treated patients (19 ± 28% reduction, p < 0.01), but was unchanged in non-treated patients (for comparison p < 0.01). The extent of platelet inhibition was unrelated to patient characteristics, including lipid profile and type of statin administered (lipophylic vs. hydrophilic). In the in vitro study platelet incubation with statin compared with PBS resulted in a lower aggregate-size (29 ± 9 µm2 vs. 39 ± 15 µm2, p < 0.01), and lower surface coverage (8.5 ± 4% vs. 12 ± 4%, p < 0.01). The effect of the statin on both parameters was significantly blunted by L-NMMA. Incubation with statin also resulted in a reduction in collagen-induced platelet aggregation (31 ± 20% vs. 54 ± 25%, p < 0.01). We concluded that in acute myocardial infarction patients, statins have an early antiplatelet effect, in addition to that afforded by standard antiplatelet therapy.

Peripheral Monocytosis following Acute Myocardial Infarction: Incidence and Its Possible Role as a Bedside Marker of the Extent of Cardiac Injury

Infiltration by mononuclear cells, mostly monocytes, into necrotic myocardial tissue can be detected beyond the 3rd day after the onset of infarction. These monocytes, mobilized by an unknown mechanism, initiate phagocytosis of necrotic tissue. We observed in patients having sustained an acute myocardial infarction (AMI) a significant increase in monocyte count 2–3 days following presentation, possibly representing peripheral recruitment of monocytes to the injured myocardium. To establish this observation, we prospectively documented monocyte and neutrophil counts throughout hospitalization in 186 consecutive patients (118 patients having sustained an AMI, 34 patients with angina, and 34 patients admitted for nonischemic reasons). Average monocyte count, which rose on the 2nd day and reached a peak on day 3, was significantly elevated in these patients compared with control subjects (p < 0.001). Neutrophil count exhibited a similar phase-shifted response. Peak monocyte count exceeded 800/mm3 (upper limit of normal range) in 69 (58%) of AMI patients but in only 3 of the 68 (4%) non-AMI patients, yielding a sensitivity and specificity of 58 and 95%, respectively, for the diagnosis of AMI by this criterion. A significant correlation between maximal creatine kinase (CK) representing the extent of myocardial necrosis and peak monocyte count was shown (r = 0.51, p < 0.0001). A correlation between CK and monocyte count sum of days 1–3 (r = 0.51, p < 0.001) was found in a substudy of 25 patients with AMI. Similarly, a correlation was shown with cardiac function score as evaluated by 2-dimensional echocardiography (p < 0.001 and p < 0.008 for difference between CK sum and monocyte count sum of high and low echo score groups, respectively). Hence, the peak monocyte count recorded during the immediate postinfarction period provides a bedside marker of the extent of myocardial damage that is the preponderant prognostic determinant. If validated in future studies this phenomenon may have diagnostic and prognostic implications.

Pulse pressure is a predictor of vascular endothelial function in middle-aged subjects with no apparent heart disease

Elevated pulse pressure (PP) is increasingly being recognized as a cardiovascular risk factor. To investigate whether PP is associated with endothelial function in subjects with no apparent heart disease we prospectively assessed brachial flow-mediated dilation (FMD) in 525 consecutive subjects with no apparent heart disease [323 (61%) men, mean age 52 ± 11I years, mean body mass index (BMI) 26 ± 4 kg/m2]. Following an overnight fast and discontinuation of all medications for ≥ 12 hours, the FMD and endothelium-independent, nitroglycerin-mediated vasodilation (NTG) were assessed using high-resolution linear array ultrasound. Univariate linear analysis revealed a significant inverse association between FMD and PP (r = —0.65, p < 0.01), systolic blood pressure (r = —0.52, p < 0.01) and age (r = —0.21, p < 0.05). Multivariate analysis showed that PP was the strongest independent predictor of FMD. We therefore divided the study population into two groups: group A (n = 290) ≤ the median PP, and group B (n = 235) > the median PP of 50 mmHg. Male sex, hypertension, diabetes, BMI, heart rate, and the use of aspirin, long-acting nitrates, calcium channel blockers, angiotensin-converting enzyme inhibitors and beta blockers were significantly more common in Group B compared with Group A. FMD but not NTG was significantly greater in patients with PP ≤ the median PP, compared with > the median PP (14.9 ± 7.9% vs 10.8 ± 8.8%, p < 0.001 and 16.1 ± 9.6% vs 14.8 ± 8.4%, p = 0.38; respectively). Thus, PP is inversely associated with brachial FMD in middle-aged subjects with no apparent heart disease, suggesting a potential mechanism whereby elevated PP contributes to cardiovascular disease. Long-term follow-up is warranted to elucidate the incidence of coronary artery disease in both study groups.