Yoseph Rozenman

Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials

BACKGROUND Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel. METHODS In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physicians discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes. FINDINGS In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopidogrel loading dose (23.2+/-19.5% vs 35.2+/-20.9%, p=0.02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69.6+/-13.5% vs 76.7+/-12.4%, p=0.054). In the TRITON-TIMI 38 trial, 13,608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0.94, 95% CI 0.80-1.11) or prasugrel (1.00, 0.84-1.20). INTERPRETATION The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel. FUNDING Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding.

Prevention of Myocardial Damage in Acute Myocardial Ischemia by Early Treatment with Intravenous Streptokinase

We evaluated the effectiveness of early intravenous administration of 750,000 units of streptokinase in 53 patients with acute myocardial ischemia treated by a mobile-care unit at home (9 patients) or in the hospital (44 patients). Treatment was begun an average (+/- S.D.) of 1.7 +/- 0.8 hours from the onset of pain. Non-Q-wave infarctions developed subsequently in eight patients, whereas all the others had typical Q-wave infarct patterns. In 81 per cent of the patients the infarct-related artery was patent at angiography performed four to nine days after admission. Vessel patency was independent of the time of treatment, but residual left ventricular function was time dependent. Patients treated less than 1.5 hours after the onset of pain had a significantly higher ejection fraction (56 +/- 15 vs. 47 +/- 14 per cent; P less than 0.05) and infarct-related regional ejection fraction (51 +/- 19 vs. 34 +/- 20 per cent; P less than 0.01) and a lower QRS score (5.6 +/- 4.9 vs. 8.6 +/- 5.5; P less than 0.01) than patients receiving treatment between 1.5 and 4 hours after the onset of pain. Patients treated earlier by the mobile-care unit also had better-preserved left ventricular function than patients treated in the hospital. We conclude that thrombolytic therapy with streptokinase is most effective if given within the first 1.5 hours after the onset of symptoms of acute myocardial infarction.

Transradial approach for coronary angiography and angioplasty.

The transradial approach has currently been advocated as an alternative catheterization method for coronary angiography and angioplasty, due to the recent miniaturization of angioplasty equipment. The purpose of this study was to assess the practical clinical applicability of this method. From June to November 1994, 100 patients underwent coronary angiography and angioplasty with the transradial approach. Their mean age was 66.6 +/- 11.2 years, and 79 were men. In 4, radial puncture was not successful, and in 3, femoral access was necessary to complete the procedure. Coronary angioplasty was performed in 63 patients (76 lesions) with angiographic success (per lesion) of 96%. In 5 patients, a stent was successfully implanted. All patients were ambulatory on the day after the angioplasty procedure. In 98% of the patients, the introducer was taken out 1 to 4 hours after the procedure by local compression using a special custom-made device. No patient required blood transfusion. Major complications occurred in 2 patients; both had a cerebrovascular accident (1 probably not procedure-related), and both recovered. A radial pulse was palpated in 91 of the patients before discharge, and in 6 others, adequate flow could be heard with Doppler. In 2 patients, radial flow was restored within several weeks. None of the patients suffered from ischemia of the hand. Two patients had a small pseudoaneurysm successfully treated by local compression. Thus, coronary angioplasty can be performed safely using the transradial approach with relatively few vascular complications and with better patient comfort. However, the procedure is more time-consuming initially compared with the transfemoral approach due to a learning curve regarding equipment selection and catheter manipulation.

Right atrial thrombi are related to indwelling central venous catheter position: Insights into time course and possible mechanism of formation

We studied the effect of central line catheters on thrombus formation in the right atrium (RA), including the incidence and echocardiographic characteristics of the catheter-associated thrombus as well as possible clinical implications in patients. We prospectively studied 55 patients by transesophageal echocardiography within 1 week after Hickman catheter implantation and on a follow-up study at 6 to 8 weeks. We succeeded in imaging the catheter tip in 48 of the 55 patients (87%). In the baseline study 13 had the tip placed in the RA, eight at the superior vena cava-atrium junction, and 27 in the superior vena cava. An abnormal mass, consistent with a thrombus, was found in 12.5% of the patients, all of which were seen within the 13-patient (46%) group with the Hickman catheter tip placed in the RA. Hickman catheter insertion is associated with high incidence (12.5%) of early formation of RA thrombus. The formation of these thrombi is asymptomatic and highly associated (p < 0.001) with the catheter tip position in the RA, in contrast to their positioning in the superior vena cava or in its junction with the right atrium. On the basis of these findings, we recommend that special attention and effort be given to placing of the catheter tip in the superior vena cava and avoiding the RA during the implantation procedure.

SPECT attenuation artifacts in normal and overweight persons : Insights from a retrospective comparison of Rb-82 positron emission tomography and TI-201 SPECT myocardial perfusion imaging

Purpose Myocardial perfusion imaging can be performed using SPECT or positron emission tomography (PET). SPECT has lower specificity than PET, largely as a result of attenuation artifacts; however, it is more widely available. The authors describe a study of the effect of sex and body weight on the incidence of SPECT attenuation artifacts using a retrospective comparison of Tl-201 SPECT and Rb PET. Methods One hundred sixty-one persons (101 men, 60 women; 81 normal weight, 80 overweight) underwent Tl-201 SPECT and Rb PET. The incidence of observed perfusion defects was studied in territories of the three major coronary arteries. SPECT and PET results were also compared with those of angiography in a subset of 75 patients. Results One hundred fourteen defects were reported on Rb PET compared with 176 defects with Tl-201 SPECT. Excess Tl-201 SPECT defects occurred in male and female, normal-weight and overweight persons. The average specificity was 64% for Tl-201 SPECT and 84% for Rb PET, reflecting this difference. Conclusions Attenuation artifacts in Tl-201 SPECT occur frequently and are not confined to easily identifiable subgroups of patients. Therefore, measures to improve specificity of SPECT (e.g., prone or gated imaging) or alternative imaging techniques such as PET have potential advantages for everyone, not simply for obese patients and women with large breasts. In addition, awareness of the prevalence of SPECT attenuation artifacts, in both sexes and all weight categories, may contribute to improved accuracy of interpretation.

One-Stage Coronary Angiography and Angioplasty

The combination of diagnostic angiography and angioplasty as a single procedure is becoming common practice in many institutions, but the feasibility and safety of this strategy have not been reported. This report describes 2,069 patients who underwent coronary angioplasty over a 3-year period at an institution where combined angiography and angioplasty is the norm. All patients were prepared before angiography for potential immediate angioplasty. In 1,719 patients, angioplasty was performed immediately after the diagnostic angiogram, while separate procedures were performed in 350 patients. Of those 350 patients, 254 were referred for angioplasty after diagnostic angiography at other hospitals. One thousand one hundred ninety-seven patients were admitted electively for treatment of stable angina pectoris, and 872 underwent procedures during hospitalization for unstable angina or acute myocardial infarction. One thousand nine hundred seven patients (92.2%) had successful angioplasties; in 130 patients (6.3%) the lesion could not be dilated, but no complication occurred, and in 32 patients (1.5%) angioplasty ended with a major complication (0.8% death, 1.0% Q-wave myocardial infarction, 0.5% emergency coronary artery bypass surgery). There was no difference between the combined and staged groups with regard to success, major and minor complication rates or in length of hospitalization after angioplasty. We conclude that routine combined strategy for angiography and angioplasty is feasible, safe, easier for the patient, and more cost-effective than 2 separate procedures.

Clinical and angiographic predictors of immediate recoil after successful coronary angioplasty and relation to late restenosis

The effect of immediate recoil on the results of balloon angioplasty was examined in a group of 416 patients (596 lesions) who underwent successful coronary angioplasty. Immediate recoil was responsible for loss of 0.42 +/- 0.64 mm from the potentially achievable lesion diameter, and represented 23% of the actual gain in diameter. The immediate recoil was determined mainly by the degree of arterial stretch, which is best represented by the balloon to normal artery size ratio (correlation coefficient 0.49, p < 0.0001). Classic risk factors for coronary artery disease did not affect immediate recoil, except for a trend toward lower values in patients with history of hypercholesterolemia. There was a tendency for lower recoil in patients with residual coronary thrombus and in those who underwent angioplasty within 1 week of acute myocardial infarction. Recoil was larger in the left anterior descending artery than in the circumflex or the right coronary artery. Patients with more immediate recoil developed more restenosis (> 50% stenosis at follow-up). However the late loss of luminal diameter due to the restenotic process was smaller in those who had larger initial recoil. It is concluded that immediate recoil after balloon angioplasty is an elastic phenomenon that is related mainly to the degree of arterial stretch. The relative importance of immediate recoil in determining the late outcome of coronary angioplasty is at least as important as the late restenotic process.

Angiographic findings in the coronary arteries after thrombolysis in acute myocardial infarction.

The angiographic appearance of the coronary arteries was examined in 308 patients with acute myocardial infarction (AMI) who received high-dose intravenous thrombolytic therapy. Coronary angiography was performed on day 7 after admission to the hospital. Patients had an average of 2.4 discrete arterial narrowings or obstructions. The narrowings were proximal and related to bifurcations. Four fifths of the culprit arteries were patient; 104 (34%) had a ruptured plaque, 22 (7%) had an ulcerated plaque, and in 190 (62%) the lesions were eccentric. Patients differed from a comparable, previously studied, control series of 302 patients with chronic stable angina pectoris who had more extensive disease. They had 5.7 narrowings/patient, also located proximally and at bifurcations, but more widely distributed in the coronary tree. Patients with AMI who are suitable for thrombolysis have a unique coronary angiographic picture. The data confirm that AMI is caused by sudden rupture of a localized atheromatous plaque that initiates an obstructive thrombotic cascade.

Relation of Thrombotic Occlusion of Coronary Stents to the indication for Stenting, Stent Size, and Anticoagulation

C oronary stents were introduced in an attempt to overcome 2 main limitations of balloon angioplasty: acute occlusion and restenosis. Numerous reports showed that different stent designs are useful.1-3 The main problem of currently available metallic stents is the tendency for thrombotic occlusion. This is a serious complication that can cause acute myocardial infarction and death.4 Chronic anticoagulation decreases the occlusion rate but causes complications at the puncture site and increases the length of hospitalization and cost of the procedure.5 Recent abstracts have suggested that anticoagulation might not be necessary when stents are deployed with high-pressure balloon inflation with or without intravascular ultrasound proof of optimal deployment.6,7 This report will describe our initial experience with PalmazSchatz stents with emphasis on the risk of thrombotic occlusion. . . . Coronary stents were successfully deployed in 50 of 52 patients (96%). In the 2 patients in whom the stent was not deployed, the procedure was successfully completed with balloon dilatation. The mean age was 60 + 11 years, most patients (45) were men, and the indication for cardiac catheterization was stable angina in 29 and unstable or postmyocardial infarction angina in 21 patients. Twenty-seven stents were implanted to overcome acute closure or severe dissection that would have otherwise required emergency bypass surgery, 14 were implanted in lesions with previous restenosis, and in 11 patients stents were implanted electively as the initial therapy (mainly in saphenous vein grafts). Thirty-nine stents were implanted in native coronary vessels and 13 in saphenous vein grafts. Stents were deployed after target lesion predilatation using a balloon that matched the size of the normal artery. Stents were manually crimped on a balloon (usually 0.5 mm larger than the original balloon) and were deployed using 30-second inflation to 6 to 8 atm. Patients were treated with intravenous dextran for 24 hours and a combination of aspirin and dipyridamole. Treatment with warfarin was begun on the day of the procedure and was continued for 3 months, with a target international normalized ratio of 3 to 4. Heparin infusion was maintained with a target partial thromboplastin time of 80 to 100 seconds for >5 days, and for 1 day after target prothrombin level was achieved. Sheaths were removed from the femoral artery the morning after the

Non-Invasive Lung IMPEDANCE-Guided Preemptive Treatment in Chronic Heart Failure Patients: A Randomized Controlled Trial (IMPEDANCE-HF Trial)

BACKGROUND Previous investigations have suggested that lung impedance (LI)-guided treatment reduces hospitalizations for acute heart failure (AHF). A single-blind 2-center trial was performed to evaluate this hypothesis (ClinicalTrials.gov-NCT01315223). METHODS The study population included 256 patients from 2 medical centers with chronic heart failure and left ventricular ejection fraction ≤35% in New York Heart Association class II-IV, who were admitted for AHF within 12 months before recruitment. Patients were randomized to a control group treated by clinical assessment and a monitored group whose therapy was also assisted by LI, and followed for at least 12 months. Noninvasive LI measurements were performed with a new high-sensitivity device. Patients, blinded to their assignment group, were scheduled for monthly visits in the outpatient clinics. The primary efficacy endpoint was AHF hospitalizations; the secondary endpoints were all-cause hospitalizations and mortality. RESULTS There were 67 vs 158 AHF hospitalizations during the first year (P < .001) and 211 vs 386 AHF hospitalizations (P < .001) during the entire follow-up among the monitored patients (48 ± 32 months) and control patients (39 ± 26 months, P = .01), respectively. During the follow-up, there were 42 and 59 deaths (hazard ratio 0.52, 95% confidence interval 0.35-0.78, P = .002) with 13 and 31 of them resulting from heart failure (hazard ratio 0.30, 95% confidence interval 0.15-0.58 P < .001) in the monitored and control groups, respectively. The incidence of noncardiovascular death was similar. CONCLUSION Our results seem to validate the concept that LI-guided preemptive treatment of chronic heart failure patients reduces hospitalizations for AHF as well as the incidence of heart failure, cardiovascular, and all-cause mortality.