Marc Cohen

Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54

AIMS Ticagrelor reduced major adverse cardiovascular event (MACE) by 15-16% in patients with prior myocardial infarction (MI) in PEGASUS-TIMI 54. We hypothesized that patients who recently discontinued P2Y12 inhibition, even years after MI, may be at particular risk of MACE and may derive particular benefit from continuation or reinitiation of therapy. METHODS AND RESULTS Patients in PEGASUS-TIMI 54 were categorized by time from last P2Y12 inhibitor (days: ≤30, >30-360, >360). The risk of MACE and the efficacy of ticagrelor were compared across categories. In the placebo arm, patients who more recently stopped P2Y12 inhibitor therapy had a greater number of risk factors but still had a higher risk of MACE after multivariable adjustment [≤30 days, hazard ratio (HR)adj 1.47, 95% confidence interval (CI) 1.12-1.93, P = 0.0051; 30 days-1 year, HRadj 1.28, 95% CI 0.98-1.67, P = 0.073] compared with those who stopped >1 year prior (P-trend = 0.0097). The benefit of ticagrelor depended on the time from last dose, with HRs (95% CI) for ticagrelor (pooled doses) vs. placebo of 0.73 (0.61-0.87), 0.86 (0.71-1.04), and 1.01 (0.80-1.27), respectively, by category (P-trend for interaction < 0.001). The benefit in those ≤30 days of stopping was similar regardless of time from MI (<2 years, HR 0.73, 95% CI 0.60-0.89 vs. ≥2 years, HR 0.71, 95% CI 0.50-1.00). CONCLUSION The benefit of ticagrelor for long-term secondary prevention in patients with prior MI and at least one additional risk factor appeared more marked in patients continuing on or re-starting after only a brief interruption of P2Y12 inhibition, when compared with patients who had proved themselves stable more than 2 years from their MI and off P2Y12 inhibitor therapy for more than a year. The increase in bleeding events with ticagrelor was similar regardless of this time interval. For clinicians considering a strategy of prolonged P2Y12 inhibitor therapy in high-risk patients, these data suggest greater benefit in the continuation of such therapy without interruption after MI, rather than re-initiating such therapy in patients who have remained stable for an extended period. Future analyses may help to clarify further the profile of post-MI patients most likely to benefit from uninterrupted dual antiplatelet therapy. CLINICAL TRIAL REGISTRATION INFORMATION http://www.clinicaltrials.gov NCT01225562.

Synergistic action of severe wall injury and shear forces on thrombus formation in arterial stenosis: Definition of a thrombotic shear rate threshold ☆

OBJECTIVES This study attempted to determine the influence of progressive degrees of stenosis on platelet deposition onto a severely damaged vessel wall. BACKGROUND The severity of wall injury and increased shear forces have been proposed as the determinants of thrombus formation and growth in arterial stenosis. METHODS Carotid angioplasty was performed in 15 mongrel dogs to produce severe wall damage. Group I (n = 9) had arteries with damage only. In group II (n = 14), progressive degrees of stenosis were produced at the center of the dilated area. Acute thrombus formation was evaluated by angiography at the time of angioplasty and platelet deposition/cm2 quantified by indium-111 labeling 1 h after the procedure. RESULTS Severe wall damage (group I) produced a significant increase in platelet deposition compared with control arterial segments (8.19 +/- 3.82 vs. 3.62 +/- 2.52 platelets x 10(6)/cm2 [mean +/- SD], p < 0.05), and the presence of a stenosis (group II) further increased platelet deposition (36.98 +/- 3.82 platelets x 10(6)/cm2, p < 0.05). Angiographic filling defects or total occlusion was found in seven of the arteries in group II but in none in group I (p < 0.05). A shear rate of approximately 5,000 s-1, corresponding to a critical stenosis of 70% and a 1.5- to 1.6-mm diameter, was found to identify the arteries in which thrombosis was likely to occur (p < 0.05). Four of 5 arteries < 1.5 to 1.6 mm in diameter had angiographic filling defects or occlusion compared with 1 of 13 with less severe stenosis (p < 0.01). CONCLUSIONS In low shear rate conditions, deep arterial injury will lead to mural thrombosis without further thrombus growth. When deep arterial injury occurs under critical local shear conditions, platelet deposition will be enhanced, and thrombosis may progress to total occlusion.

Efficacy and safety of ticagrelor for long-term secondary prevention of atherothrombotic events in relation to renal function: insights from the PEGASUS-TIMI 54 trial

AIMS We evaluated the relationship of renal function and ischaemic and bleeding risk as well as the efficacy and safety of ticagrelor in stable patients with prior myocardial infarction (MI). METHODS AND RESULTS Patients with a history of MI 1-3 years prior from PEGASUS-TIMI 54 were stratified based on estimated glomerular filtration rate (eGFR), with <60 mL/min/1.73 m(2) pre-specified for analysis of the effect of ticagrelor on the primary efficacy composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events, MACE) and the primary safety endpoint of TIMI major bleeding. Of 20 898 patients, those with eGFR <60 (N = 4849, 23.2%) had a greater risk of MACE at 3 years relative to those without, which remained significant after multivariable adjustment (hazard ratio, HRadj 1.54, 95% confidence interval, CI 1.27-1.85, P < 0.001). The relative risk reduction in MACE with ticagrelor was similar in those with eGFR <60 (ticagrelor pooled vs. placebo: HR 0.81; 95% CI 0.68-0.96) vs. ≥60 (HR 0.88; 95% CI 0.77-1.00, Pinteraction = 0.44). However, due to the greater absolute risk in the former group, the absolute risk reduction with ticagrelor was higher: 2.7 vs. 0.63%. Bleeding tended to occur more frequently in patients with renal dysfunction. The absolute increase in TIMI major bleeding with ticagrelor was similar in those with and without eGFR <60 (1.19 vs. 1.43%), whereas the excess of minor bleeding tended to be more pronounced (1.93 vs. 0.69%). CONCLUSION In patients with a history of MI, patients with renal dysfunction are at increased risk of MACE and consequently experience a particularly robust absolute risk reduction with long-term treatment with ticagrelor.

Ureaplasma urealyticum (T-mycoplasma) infection: does it have a role in male infertility?

Ureplasma urealyticum (T-mycoplasma) has been related to male infertility by some observers. To assess further this question 150 couples who presented for fertility had semen and cervical mucus cultures for mycoplasma. Positive cultures were obtained from 69 couples. There were no significant differences in the semen analyses among patients with positive or negative cultures. The presence of mycoplasma in the semen is probably the result of contamination at the time of ejaculation. Routine investigation for the presence of mycoplasma in subfertile men is unjustified. The routine use of broad-spectrum antibiotics in subfertile patients with positive mycoplasma culture is unnecessary.

Antiplatelet therapy in percutaneous coronary intervention: A critical review of the 2007 AHA/ACC/SCAI guidelines and beyond

Antiplatelet therapy is a mainstay in the treatment of patients who have undergone percutaneous coronary intervention (PCI). Although the 2007 PCI treatment guidelines were published by the American College of Cardiology, the American Heart Association, and the Society for Cardiovascular Angiography and Interventions, new clinical evidence has emerged, expanding our understanding of antiplatelet use and potentially affecting the treatment guidelines. For example, clinical trial results prompted a Science Advisory to recommend that dual therapy with aspirin and clopidogrel be used for longer periods—up to 1 year in patients who receive bare metal stents and at least 1 year in patients receiving drug‐eluting stents. New trial results have also emerged regarding the use of glycoprotein IIb/IIIa antagonists such as abciximab, eptifibatide, and tirofiban. This article reviews the current recommendations for antiplatelet therapy in PCI patients, recent trial results, newly developed agents, ongoing clinical trials, and the future direction of antiplatelet therapy in patients who undergo PCI.

Regression in thromboembolic type of primary pulmonary hypertension during 2½ years of antithrombotic therapy

Primary pulmonary hypertension carries a poor prognosis, with a 5 year survival rate of less than 25%. However, a previous study of more than 100 patients with tissue-proved primary pulmonary hypertension suggested that antithrombotic therapy may have a beneficial effect on survival, especially in patients with the thromboembolic type of primary pulmonary hypertension. This report describes a 54 year old white man with primary pulmonary hypertension of the thromboembolic type (proved by right upper lobe lung biopsy) who, after long-term antithrombotic therapy, showed resolution of symptoms of dyspnea and fatigue, regression of electrocardiographic signs of right ventricular hypertrophy and regression of elevated pulmonary artery pressure. Base-line cardiac catheterization in January 1982 revealed elevated pulmonary artery pressure (104/37 mm Hg) and pulmonary vascular resistance (14.6 units/m2) that did not decrease with 100% oxygen or intravenous hydralazine (12 mg). The patient was treated with warfarin and dipyridamole, 100 mg four times daily. The most recent cardiac catheterization in January 1984 revealed a pulmonary artery pressure of 50/15 mm Hg and a pulmonary vascular resistance of 8.7 units/m2. It is believed that this is the first report of regression of the symptoms and signs of biopsy-proved primary pulmonary hypertension. In view of the lack of a response to vasodilators in 1982, it is suggested that antithrombotic therapy is partially responsible for the improvement of this patient.

Response of the right ventricle to exercise in isolated mitral stenosis

Eight patients in sinus rhythm, with varying degrees of isolated mitral stenosis (mitral valve area 0.6 to 1.3 cm2 and total pulmonary vascular resistance 5.0 to 17.5 U-m2), underwent supine rest and symptom-limited exercise radionuclide ventriculography to determine right ventricular (RV) and left ventricular ejection fraction (EF). Cardiac catheterization with hemodynamic measurements at rest and at peak exercise was performed within 24 hours of radionuclide ventriculography. Four of the 8 patients underwent corrective mitral surgery resulting in normal mean pulmonary artery pressures and total pulmonary vascular resistance at rest. These 4 patients had repeat radionuclide ventriculography at rest and during exercise 1 to 2 months after surgery. Preoperatively, all 8 patients had an abnormal exercise RVEF response (mean change +/- standard deviation [SD], -5.0 +/- 4.5%), coincident with an increase in mean pulmonary artery pressure during exercise (mean change, 15 +/- 5.0 mm Hg). The change in RVEF from rest to exercise, corrected for duration of exercise, correlated with peak exercise mean pulmonary artery pressure (r = -0.71, p = 0.05), as well as total pulmonary vascular resistance at rest (r = -0.82, p = 0.02). Postoperatively, all 4 patients who underwent surgical correction showed a normal RVEF response during exercise (mean change +/- SD, +6.8 +/- 4.0%). Thus, in patients with acquired mitral stenosis and no coronary artery disease (1) loading conditions and not contractility are prime determinants of RV exercise response, and (2) an exercise-induced decrease in RVEF may be a sensitive marker for increased total pulmonary vascular resistance and pulmonary hypertension.

Thrombolytic therapy in acute myocardial infarction: Review of clinical trials

Intracoronary infusion of streptokinase is associated with recanalization rates of 60 to 90% immediately after the procedure. Mortality data in published trials are conflicting. In 125 registry patients who had paired contrast ventriculograms before streptokinase infusion and hospital discharge, improvement in ejection fraction correlated with incomplete coronary obstruction before angiography, the presence of collateral vessels to the infarct area and recanalization of complete obstruction. In assessing the risk/benefit ratio of intracoronary streptokinase infusion, the risks of angiography in the setting of acute myocardial infarction, reocclusion, bleeding and such secondary interventions as angioplasty or bypass surgery must be considered. Intravenous infusion of conventional doses of streptokinase was associated with improved survival in some trials in which therapy began within 12 hours after the onset of infarction. Immediate recanalization rates in patients who received large doses of intravenous streptokinase were lower than those associated with intracoronary streptokinase infusion. The risks and benefits of high-dose intravenous streptokinase administration must still be assessed.

Insights into the pathogenetic mechanisms of unstable angina.

Patients with unstable angina and/or non-Q-wave infarction constitute a group that is at high risk for progression to acute myocardial infarction or sudden death. Furthermore, in spite of maximal medical therapy, a large fraction of these patients experience recurrent episodes of myocardial ischemia prompting surgical revascularization or coronary angioplasty. In prior studies of patients with unstable angina, the incidence of myocardial infarction within 1 month of hospitalization was 8-13%, and the incidence of death was about 4%. Between 3 months and 1 year after presentation, the cumulative rate of infarction or death increased to 10-14 and 8-10%, respectively. That is, most recurrent ischemic events occur within the first 3 months after the onset of symptoms. In the subset of patients with pain at rest or with electrocardiographic changes at the time of admission, the prognosis is even worse. The rate of myocardial infarction or death in such patients ranged between 14 and 21% during the first 3-4 months after onset of symptoms. Crossover to surgical therapy because of recurrent ischemic pain was also common, occurring in 30-50% of the patients at 3 months. Recent advances in understanding the pathophysiology of these two syndromes suggest that an aggressive antithrombotic regimen could be of great benefit in preventing progression to acute coronary occlusion and death. Pathologic investigations strongly suggested that plaque fissuring and subsequent overlying thrombosis were the major components in the process of unstable angina progressing to myocardial infarction and/or sudden death. This hypothesis has been substantiated by recent pathologic studies of patients who died shortly after the onset of unstable angina. Examination of the coronary arteries revealed not only plaque fissuring with superimposed layers of thrombus in the majority of the cases, but also evidence of distal thromboembolism from these foci. In vivo coronary arteriography in patients with unstable angina highlighted the progression of prior coronary stenoses, even to total occlusion, and the eccentric and irregular angiographic morphology of the ischemia-producing lesions. Furthermore, intracoronary thrombus is often seen at these sites, especially when arteriography is carried out soon after rest pain. These observations also suggested that plaque rupture may have occurred. Intraoperative angioscopy has revealed ruptured plaques in patients with progressive unstable angina, while those with rest pain had complicating thrombi. Patients with unstable angina also have biochemical evidence of activation of both the coagulation systems and platelets.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment strategies in non-ST-elevation acute coronary syndromes in patients undergoing percutaneous coronary intervention: an evidence-based review of clinical trial results and treatment guidelines: report on a roundtable discussion.

With the availability of new data and the recent release of new European and US guidelines, contemporary care paradigms for the treatment of patients with non-ST-elevation acute coronary syndromes (NSTE ACS), including those undergoing percutaneous coronary intervention, are likely to undergo substantial changes. In recognition of this shifting landscape as well as the impact of new guidelines on care models for the treatment of patients with NSTE ACS, a roundtable was convened on October 25, 2007, to discuss the implications of these changes. The purpose of this review is to summarize the presentations and subsequent discussions from the roundtable, which examined the guidelines and evidence from a variety of perspectives, and to explore the best ways to incorporate new treatment paradigms into everyday clinical care. The multiple viewpoints expressed by the roundtable attendees illustrate the recognition that at this point, consensus has not been reached on the optimum algorithm for treatment of these patients. This article focuses on issues discussed during the roundtable from the perspective of the practicing cardiologist.