(Circulation. 1995;92:693-696.)
© 1995 American Heart Association, Inc.
Articles |
American College of Cardiology Meeting Highlights
From St Luke's Episcopal Hospital, Texas Heart Institute, Baylor College of Medicine, and the University of Texas Health Science Center at Houston.
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Heparin-Coated Stents: The BENESTENT Study |
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 Top Heparin-Coated Stents: The... Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr Patrick Serruys from the Thoraxcenter in Rotterdam presented the preliminary results of the BENESTENT II pilot study, a trial designed to evaluate the safety of reducing or eliminating anticoagulant therapy in patients treated with heparin-coated balloon-expandable coronary stents.
The trial was designed in four sequential phases: in phase I, heparin was reinstituted 6 hours after sheath removal, followed by coumadin; in phase II, heparin therapy resumed 12 hours after sheath removal, also followed by coumadin; in phase III, heparin therapy resumed 18 hours after sheath removal, again followed by coumadin; and in phase IV, heparin and coumadin were not used after sheath removal—rather, patients were treated with ticlopidine. Patients in all four groups received aspirin (250 mg/d), dipyridamole (75 mg TID), and diltiazem (120 mg BID). Dextran was administered perioperatively, procedural heparin was administered according to activated coagulation times, and heparin-coated Palmaz-Schatz balloon-expandable stents were used. Vein graft lesions were excluded from the study.
A total of 207 patients were enrolled at 32 clinical centers; 202 patients underwent stent placement. Enrollment commenced in February 1994 and ended in November 1994. There were no instances of stent thrombosis in any of the groups. The incidence of vascular surgery (5.9%, 4.1%, 2.0%, and 0% in groups I, II, III, and IV, respectively) and blood transfusion (2.0%, 0%, 2.0% and 0% in groups I, II, III, and IV) declined with less intense anticoagulation. In-hospital lengths of stay were reduced dramatically from 7.4 days in group 1 to 3.0 days in group IV.
Dr Serruys concluded that progressively delaying heparin resumption and coumadin therapy after sheath removal (to the point of replacing it entirely with antiplatelet agents) has virtually eliminated major bleeding complications and dramatically reduced the length of in-hospital stays. Despite less intense anticoagulation, there was no stent thrombosis in these patients who received heparin-coated stents.
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Radioactive Stents |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr Christophr Hehrlein and coworkers from the University of Heidelberg and the Karlsruhe Nuclear Research Center in Germany presented their very interesting experiences with radioactive stents. They used radioactive Palmaz-Schatz stents with a very low activity (17.5 µCi) in a total of 20 rabbit arteries. The absorbed radiation dose a distance of 10 to 11 mm outward from the stents after 100 days was less than the human chest radiation dose from a cardiac catheterization procedure. The investigators compared smooth muscle cell proliferation and neointimal hyperplasia at 1 and 12 weeks after implantation of both radioactive and nonradioactive stents. The degree of smooth muscle cell proliferation was assessed with immunostaining for proliferating cell nuclear antigen (PCNA), and the degree of neointimal hyperplasia was assessed by computer-assisted counting of neointimal cells. At 1 week, radioactive stents had 0.5% PCNA-positive smooth muscle cells compared with 30% PCNA-positive smooth muscle cells in nonradioactive stents. After 12 weeks, there were more than three times fewer neointimal cells found with radioactive stents, and the neointimal area was significantly reduced (0.4±0.2 versus 0.8±0.2 mm2). Dr Hehrlein concluded that low-dose endovascular radiation with radioactive stents appears to reduce smooth muscle cell proliferation and neointimal thickening after angioplasty.
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Primary Angioplasty for Acute Myocardial Infarction: Early Discharge of Low-Risk Patients |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr Bruce Brodie from The Moses H. Cone Memorial Hospital in Greensboro, NC, presented the results of the low-risk patient arm of the PAMI-2 study. PAMI-2 is a prospective, randomized trial of patients with acute myocardial infarction undergoing primary percutaneous transluminal coronary angioplasty (PTCA), evaluating both early (day 3) discharge in low-risk patients (n=471) and intra-aortic balloon pumping in high-risk patients (n=437). Low-risk patients were younger; had a lower incidence of prior infarction, prior bypass surgery, and anterior infarction; and also had higher left ventricular ejection fractions. As predicted, low-risk patients had a significantly lower incidence of major cardiovascular events. From the perspective of baseline variables, low-risk patients randomized to early discharge (admission to a stepdown unit after PTCA; discharge targeted for day 3) had a slightly lower incidence of anterior infarction than low-risk patients randomized to standard care (admission to the cardiac care unit, discharge targeted for days 5 to 7).
There were no significant differences in in-hospital event rates for the two low-risk groups. Of the 234 patients randomized to early discharge, 61% were discharged on or before day 3, and 85% were discharged by day 5. The mean hospital length of stay was 4.2±2.3 days in comparison with a mean hospital length of stay of 7.0±4.3 days in the standard care group. Readmission within 1 week was infrequent in both groups; there were no patients with death, reinfarction, or repeat intervention in the early (1 week) follow-up period. Long-term follow-up data are pending. Preliminary cost data from The Moses H. Cone Memorial Hospital and William Beaumont Hospital showed significantly lower hospital costs in patients randomized to early discharge.
Dr Brodie concluded that (1) catheterization data can be used to stratify patients into low- and high-risk groups, (2) low-risk patients have a low incidence of untoward events, (3) event rates are similar for early discharge and standard care patients, and (4) early discharge appears safe, may be applied to more than 40% of patients with acute myocardial infarction treated with primary PTCA, and is associated with significant reduction in hospital length of stay and hospital costs.
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Amlodipine in Heart Failure |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr Milton Packer from Columbia College of Physicians and Surgeons in New York City presented the results of the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) study, a randomized placebo-controlled trial of amlodipine in 1153 patients at 105 centers in the United States and Canada. Eighty percent of the patients had class III heart failure; the average ejection fraction was 21%. The mean follow-up period for the study was 14.4 months. The primary end point of the study was the combined incidence of death and hospitalization for a life-threatening cardiovascular event. A total of 732 patients were enrolled with heart failure resulting from coronary artery disease; 421 had nonischemic dilated cardiomyopathy. There was a nonsignificant trend in the total study cohort in favor of lower total event rates and lower mortality in the amlodipine group.
Amlodipine had no effect on the primary combined end point or total mortality in patients with coronary artery disease, whereas in patients with nonischemic dilated cardiomyopathy, amlodipine treatment resulted in a 31% relative reduction in the primary combined end point and a 45% reduction in death. Dr Packer concluded that amlodipine is well tolerated in patients with class III or IV heart failure, but the effects appear to depend on the cause of heart failure. It does not favorably affect outcome in patients with ischemic heart failure but may be beneficial in patients with nonischemic dilated cardiomyopathy.
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Oral D-Sotalol: The SWORD Study |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr Albert Waldo from Case Western Reserve University in Cleveland, Ohio, presented the results of the Survival With Oral D-Sotalol (SWORD) study on behalf of the SWORD Study Investigators. This trial was originally designed to enroll 6400 patients in a randomized study comparing D-sotalol (100 mg BID; 200 mg BID if tolerated) with placebo in patients with a left ventricular ejection fraction of
40% and a recent (6 to
42 days) myocardial infarction or a remote (>42 days) myocardial
infarction with class II or III heart failure. Follow-up was to be
continued for 18 months. The trial was stopped prematurely on November 1, 1995, after 3119 patients had been enrolled (with a mean follow-up of 156 days) because of an excess in mortality in the D-sotalol group. There were 42 deaths (2.7%) in the placebo group compared with 71 (4.6%) in the D-sotalol group (P=.005). There were no significant differences in baseline characteristics between the two treatment groups. In the overall group, the mean ejection fraction was 30.8%; 29.2% of patients had a recent myocardial infarction, whereas 70.8% had a remote myocardial infarction. Dr Waldo concluded that prophylactic therapy with oral D-sotalol is associated with significantly increased mortality in a population of post–myocardial infarction patients with left ventricular dysfunction.
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Unfractionated Heparin, Low-Molecular-Weight Heparin, and Aspirin for Unstable Angina |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr Enrique Gurfinkel from the Favoloro Foundation in Buenos Aires, Argentina, reported on a randomized trial comparing aspirin alone, aspirin plus unfractionated heparin (titrated to the activated partial thrombin time), and aspirin plus low-molecular-weight heparin (214 UC/kg anti-Xa BID) in 205 patients with unstable angina (rest pain within 24 hours before admission). Primary study end points included (1) 12-lead Holter monitoring for silent ischemia, (2) recurrent angina, (3) acute myocardial infarction, (4) urgent intervention (angioplasty or bypass surgery), (5) major bleeding, and (6) death. Patients treated with aspirin plus low-molecular-weight heparin had significantly fewer silent ischemic episodes (27%) than the aspirin-alone group (60%) or the unfractionated-heparin group (61%). Similarly, they had fewer recurrent anginal episodes (9%) than the aspirin-alone group (19%) or the unfractionated-heparin group (26%). There were no myocardial infarctions and no urgent interventions in the low-molecular-weight heparin group, but the overall event rates for these end points were relatively low. Minor bleeding occurred in 10 unfractionated-heparin patients, 1 low-molecular-weight heparin patient, and no aspirin patients. There was 1 unfractionated-heparin patient with a major bleed and no deaths in any of the three groups. Dr Gurfinkel concluded that treatment with aspirin and high-dose low-molecular-weight heparin was associated with significantly better clinical outcomes than aspirin alone or aspirin plus unfractionated heparin.
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Magnesium Therapy in Unstable Angina |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr Simon Redwood from St George's Hospital in London, England, presented the results of a randomized, placebo-controlled study of magnesium therapy in unstable angina. A total of 62 patients with unstable angina were randomized to receive either magnesium (8-mmol bolus, 3 mmol/h for 24 hours) or placebo. All patients had rest pain within 24 hours before admission, ischemic ST-T changes, and normal admission creatine kinase (CK) levels. Study drug therapy was initiated within 12 hours of admission. Unless contraindicated, all patients received aspirin, ß-blockers, intravenous nitrates, and heparin. The total CK-MB release was significantly lower in the magnesium group at 6 and 24 hours. Regression of T-wave changes also occurred more frequently at 24 hours in the magnesium group. Forty-eight-hour Holter monitor studies demonstrated a similar proportion of patients in the placebo group (48%) and magnesium group (52%) with transient ischemic episodes. However, the magnesium group had significantly fewer total episodes (57 versus 118) and a trend toward shorter episodes. Urinary epinephrine excretion was also significantly lower in the magnesium group (1.65±0.20 versus 1.61±0.41 ng/mmol creatine), although norepinephrine secretion and ß-thromboglobulin did not differ between groups. Dr Redwood concluded that magnesium appears to have potentially beneficial effects in addition to standard therapy and that further studies are warranted to investigate the effects of magnesium on mortality in patients with unstable angina.
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7E3, Low-Dose Heparin, and Early Sheath Removal for PTCA |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr Michael Lincoff from the Cleveland Clinic in Cleveland, Ohio, presented the results of the PROLOG study, a multicenter pilot trial evaluating the safety and efficacy of weight-adjusted heparin dosing and early sheath removal in PTCA patients treated with the platelet glycoprotein IIb/IIIa receptor antibody 7E3. A total of 103 patients undergoing PTCA treated with 7E3 (0.25 mg/kg per bolus, 10 µg/min infusion for 12 hours) were randomized to one of two possible heparin regimens—either "standard-dose" weight-adjusted heparin (100 U/kg bolus, titrated to an ACT of 300 to 350 seconds) or "low-dose" weight-adjusted heparin (70 U/kg bolus, without ACT-guided titration)—and one of two possible sheath removal strategies—early (immediately after procedural heparin had worn off) or 12 hours after the procedure. The median preinflation ACT in the standard-dose heparin arm was 330 seconds; in the low-dose heparin arm, it was 257 seconds. Hematoma formation and transfusion requirements were significantly lower in the low-dose heparin group, and all bleeding complications were significantly reduced in the early sheath removal group. There were no increases in ischemic complications in the low-dose heparin group. Dr Lincoff concluded that reduced weight-adjusted heparin dosing in conjunction with the antiplatelet antibody 7E3 appeared to decrease bleeding complications without increasing the incidence of ischemic events. Early sheath removal is feasible even when IIb/IIIa antagonists are used and appears to also result in significantly fewer local bleeding complications.
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Mechanisms of Arterial Response After Transcatheter Therapy |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr Gary Mintz from the Washington Hospital Center in Washington, DC, presented data from an intravascular ultrasound study examining the mechanisms of the late arterial response to transcatheter therapy. They analyzed serial measurements of angiographic minimal lumen diameter (MLD) and diameter stenosis and intravascular ultrasound measurements of external elastic membrane (EEM), lumen, and plaque area in 137 lesions treated with a variety of different therapeutic modalities (31 angioplasty, 57 directional atherectomy, 26 rotational atherectomy, and 23 excimer laser angioplasty). On the basis of serial angiographic studies (mean of 4.7±2.8 months after the procedure), there were 14 lesions in whom the MLD increased, 44 lesions in whom the MLD decreased with a final diameter stenosis <50%, and 79 lesions in whom the MLD decreased with a final diameter stenosis of >50%. The degree of ultrasound measured late lumen loss, geometric remodeling (change in EEM area), and tissue growth (change in plaque areas) was compared between groups. Geometric remodeling was correlated with the degree of tissue growth (r=.426, P<.0001) but was independent of the type of intervention used. Late lumen gain was found to be the result of "overcompensation," with an increase in EEM area and minimal tissue growth. Late lumen loss without angiographic restenosis was associated with modest tissue growth and no increase in EEM area. Angiographic restenosis was associated with moderate tissue growth and a significant degree of geometric remodeling, which contributed about 66% of the total late lumen area loss. Dr Mintz concluded that the patterns of late arterial response after transcatheter coronary interventions are determined more by the direction and magnitude of geometric remodeling than by the degree of tissue growth.
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Electroporated Platelets for Drug Delivery |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Two presentations reported the use of electroporated platelets as a novel local drug delivery system. When platelets are exposed to a sequence of high-voltage discharges, electric field–induced membrane pores are opened, and compounds can be incorporated within the platelet itself. When platelets aggregate at the site of arterial injury, the incorporated compounds are brought to the injured area by the treated platelets themselves.
Samuel Ward and coworkers from the Cleveland Clinic in Cleveland, Ohio, and the Royal Free Hospital in London, UK, evaluated electroporated platelets as a vehicle for delivering the prostacyclin analogue Iloprost to areas of balloon-induced arterial injury in normal and atherosclerotic rabbit femoral arteries. The injury sites were treated with either untreated platelets, sham-treated platelets (electroporated without drug loading), or Iloprost-loaded electroporated platelets. The degree of platelet deposition was quantified with 111In-labeled platelets that had been infused 30 minutes before balloon injury. The Iloprost-treated segments had a 48% and 64% relative reduction in the degree of platelet deposition, respectively, in normal and atherosclerotic segments. Dr Ward concluded that this unique "piggy-back" delivery system is capable of delivering compounds locally, which can reduce platelet deposition at sites of arterial injury.
Dr Adrian Banning and coworkers from Royal Free Hospital in London, UK, and University Hospital of Wales, Cardiff, Wales, UK, also used electroporated Iloprost-loaded platelets in the setting of balloon-induced carotid injury in pigs. Four treatment groups were compared: (1) local infusion of Iloprost-loaded platelets, (2) intravenous administration of Iloprost-loaded platelets, (3) local infusion of sham-treated platelets, and (4) local infusion of sham-treated platelets with free Iloprost. Treated sites were histologically examined and classified as either minimal or deep (ruptured internal elastic lamina) injury. The degree of platelet deposition at the treated arterial site was ascertained with 111In-labeled platelets administered before balloon injury. There was significantly lower amounts of platelet deposition at deep arterial injury segments treated with Iloprost-loaded platelets, particularly so when the platelets were delivered locally. Dr Banning concluded that electroporated platelets can be used to deliver Iloprost to injured arterial segments and that this treatment results in decreased platelet adhesion at sites of deep arterial injury, particularly so when Iloprost-loaded platelets are delivered locally.
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Recombinant Plasminogen Activator for Acute Myocardial Infarction |
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TopHeparin-Coated Stents: The...Radioactive Stents Primary Angioplasty for Acute...Amlodipine in Heart Failure...Oral D...Unfractionated Heparin, Low...Magnesium Therapy in Unstable...7E3, Low-Dose Heparin, and...Mechanisms of Arterial Response...Electroporated Platelets for...Recombinant Plasminogen... |
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Dr John Hampton from University Hospital in Nottingham, England, presented the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial. The purpose of this study was to determine whether reteplase (a new recombinant plasminogen activator) is at least equal to streptokinase for the treatment of patients with acute myocardial infarction. The INJECT Trial is the first major cardiovascular trial to use "equivalence" to define the primary end point. Reteplase, unlike alteplase (single-chain tissue-type plasminogen activator [TPA]) and duteplase (double-chain TPA) possesses only the kringle-2-domain and protease domains of TPA, with no glycosidic side chains. This results in a longer half-life of the compound and allows for easier administration with bolus or double-bolus regimens.
A total of 6010 patients from 108 clinical centers in nine countries were enrolled in the trial. To qualify for inclusion, patients had to have symptoms and ECG criteria consistent with an acute myocardial infarction and had to receive treatment within 12 hours of the onset of symptoms. Qualifying patients were randomized to receive either streptokinase (1.5 MU over 60 minutes) or reteplase (2 boluses of 10 MU, 30 minutes apart). All patients received intravenous heparin for at least 24 hours after thrombolytic treatment. The primary end point of the study was 35-day outcome.
For all patients enrolled, there was a nonsignificant trend toward lower 35-day mortality in the reteplase group (9.02%) compared with the streptokinase group (9.53%) (95% confidence interval, -1.98%, 0.96%). For all patients in whom study drug was actually initiated, the 35-day mortality was significantly lower in the reteplase group (8.90%) than in the streptokinase group (9.43%). The incidence of in-hospital stroke was 1.23% for reteplase and 1.00% for streptokinase. Bleeding events were similar for the two treatment groups: 0.79% in the reteplase group required transfusion compared to 1.0% in the streptokinase group. The incidence of recurrent myocardial infarction was similar between groups, but the incidence of other complications (atrial fibrillation, asystole, shock, heart failure, and hypotension) was significantly lower in the reteplase group.
Dr Hampton concluded that reteplase is an effective drug for the treatment of acute myocardial infarction and is at least equal to streptokinase; it will be a useful addition to our therapeutic armamentarium.
Received June 28, 1995; accepted June 28, 1995.
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