Session highlights from the American College of Cardiology Scientific Sessions: March 29 to April 1, 1998

Session highlights from the American College of Cardiology Scientific Sessions: March 29 to April 1, 1998 John H.Alexander,MD, Adam B.Greenbaum,MD, Michael P.Hudson, MD, David F. Kong, MD,Julie M.Miller, MD, Chen Y.Thng, MD,and David}.Whellan,MD Durham, N.C

Session

Acute Ischemic Heart Disease Session

New Studies Using Platelet ReceptorAntagonists

New Understandings ofAnticoagulation During Unstable Angina

Study: Thrombocytopenia in a Large, International Trial

Study: Hirudin Reduces Death and Myocardial

of the GPIIb/Illa Inhibitor Eptlfibatide in Patients With Acute Coronary Syndromes

Reinfarction at Six Months: Follow-up Results of the GUSTO lIb Trial

Presenter: MatthewW: McClure, Duke Clinical Research Institute, Durham, N.C.

Presenter: Christopher B.Granger, Duke University Medical Center, Durham, N.C.

Results: This paper detailed the ~month results of the GUSTO-lIb trial. GUSTO-lIb randomly assigned 12,142 patients with acute coronary syndromes to the direct anti-thrombin hirudin or heparin in conjunction with aspirin and fibrinolytic therapy for those with ST elevation.At 30 days patients randomly assigned to hirudin had a 10.2% reduction in death or myocardial infarc· tion (MI) (9.8% vs 8.9%,P = 0.058). For patients with ST-segment elevation, hirudin appeared to have a greater effect in patients who received streptokinase compared with those who received TPA.At 6 months patients receiving hirudin had a 5.0% reduction in death (7.0% vs 7.3%,P = not significant [NS)), a 13% reduction in MI (7.1% vs 8.2%,P 0.035), and a 10% reduction in death or MI (12.3% vs 13.6%,p =0.039). There was a slightly greater beneficial effect seen in patients with ST-segment elevation, particularly in those receiving streptokinase.

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Interpretation: The modest beneficial effects of the direct antl-thrombln hirudin in patients with acute coronary syndromes are preserved over time. Whether hirudin has greater effect in patients with ST elevation who receive streptokinase will require further study.

From the Division of Cardiology, Department of Medicine, Duke University Medical Center. Am HeartJ 1998;135:1099.114. Copyright C> 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/9OP79

Results: This poster concerned the incidence of and outcomes associated with thrombocytopenia (platelet count
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moderate/severe bleeding (OR 2.2,p < 0.00(1) and higher incidence of 3D-day death or myocardial infarction (OR 1.3,P 0.015).

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Interpretation: This poster reports the largest experience to date with thrombocytopenia in non-ST-elevation acute coronary syndromes and with the GPIIblllla inhibitor eptifibatide.The incidence of severe/profound thrombocytopenia with this agent appears to be low and in the range reported with other GPIIbIllla inhibitors. Thrombocytopenia is clearly associated with worse outcomes; whether thrombocytopenia is the cause of these events, however, is difficult to determine from these data.

Special Session Late-Breaking Clinical Trials II

Study: Direct Antithrombin-Argatroban in Acute Myocardial Infarction (ARGAMl-2) Presenter: E1ieser Kaplinsky, Sheba Medical Center,TelHashomer, Israel

Results: The self-promoting and platelet-activating properties of thrombin have prompted interest in direct antithrombin agents in the setting of myocardial infarction. Early studies suggested that argatroban may accelerate reperfusion, particular1y when given within 3 hours of symptom onset.TheARGAMl-2 trial examined argatroban versus heparin in patients receiving thrombolytic therapy for myocardial inWction.The primary purpose of the trial was to evaluate the safety of argatroban in this setting. The study design planned to randomize 1200 patients with chest discomfort ~30 minutes and <6 hours into 3 arms. The high-dose argatroban arm consisted of a 120 mg bolus followed by 4 mg/kg/min for 72 hours.The low-dose argatroban arm used half the dose (60 mg bolus plus 2 mg/kg/min for 72 hours). Patients randomly assigned to the heparin control ann received a 5000 U heparin bolus followed by 1000 U/hr. Patients received concomitant streptokinase (1.5 million U infused over a I-hour period) orTPA therapy (front-loaded 100 mg over a 9O-minute period) in a network of 25 Israeli hospitals. Exclusion criteria included central nervous system events, chronic illness, elevated creatinine level, and risk of bleeding events.The study was powered for a 30% reduction in end point event rates. Efficacy end points were 3O
had been enrolled.A significant difference in mortality rate was discovered between the low-dose argatroban group (20 deaths/l99 patients), and the heparin control arm a deaths/209 patients).There were 14 deaths in the 201 patients assigned to the high-dose argatroban arm. The low-dose argatroban arm was stopped, and the two remaining arms continued enrollment in a blinded fashion.At the end of the trial, 494 patients had been randomly assigned to the high-dose argatroban ann, and 209 patients had been assigned to the heparin control ann. Safety end points included two major bleeds in the highdose argatroban group compared with six major bleeds in the heparin arm.Two of the major bleeds in the heparin arm were intracranial hemorrhages; there were no intracranial hemorrhages in the high-dose argatroban group.The incidence of minor bleeds was not statistically different between the two arms (27 argatroban, 36 heparin).The overall incidence of bleeding was 5.9% for the high-dose argatroban arm and 8.3% for the heparin group. For the efficacy end points, there was no significant difference between the two arms in death (high-dose argatroban 6.1 % vs heparin 4.5%), reinfarction (2.6% vs 3.4%), heart failure (6.5% vs 5.1 %), interventions (9.5% vs 9.3%), or ischemic stroke (0.2% vs 1.0%).

Interpretation: There was a lower incidence of major and minor bleeds in the argatroban group compared with the heparin group and no mortality rate difference between the high-dose argatroban group and the heparin group. Direct thrombin inhibitors appear to be similar in safety to unfractionated heparin and warrant further study as an adjunct to thrombolytic therapy.

Session New Studies Using Platelet Receptor Antagonists

Study: Primary Reperfusion inAcute Myocardial Infarction With ReoPro and Heparin: Interim Results of ReoMIStudy Presenter: R. Makkar, Cedars-Sinai Medical Center, Los Angeles, Calif.

Results: Dr.Makkar presented interim data from the ReoMI Study (ReoPro in Myocardial Infarction) investigating the use of the glycoprotein Ilb/Illa receptor blocker abciximab in acute ST-segment elevation myocardial infarction.Thirty-four subjects.were collected from five us. centers and studied prospectively in this nonrandom-

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ized pilot study. Enrollment criteria were age >21 years, electrocardiographic ST-segment elevation, <6 hour interval from chest pain onset, and eligibility for primary angioplasty.All patients were treated initially with aspirin (325 mg), intravenous heparin (70 U/kg) and intravenous ReoPro (0.25 mg/kg bolus and 0.10 mg/min infusion). Patients were then emergently studied in the catheterization lab for primary outcome of mfarct-related artery patency (Thrombolysis in Myocardial Infarction [TIMI] 2/3 flow) at a mean of 34 minutes after ReoPro dosing. Thirty-two (94%) patients underwent primary percutaneous transluminal coronary angioplasty, and in-hospital clinical outcome data were collected. The abcixirnab plus heparin combination produced infarct-related artery patency rates of 55%, 21%, 12%,and 13% forTIMI flow grades 0,1, 2,and 3,respectively.Thus 25% of patients achieved the primary outcome ofTIMI 2 or 3 flow. Further analysis of data suggested that reperfusion was improved as the time between the abciximab bolus and catheterization increased. Fifty percent of patients undergoing catheterization >45 minutes after abciximab attaInedTIMI 2/3 flow versus 15% among those with earlier catheterizatlons.The coronary intervention was successful in 97% of cases and there was an overall 94% rate of freedom from in-hospital death, recurrent myocardial infarction, or repeat revascularization.

Interpretation: This small, nonrandomized pilot trial demonstrates that abcixirnab may safely be administered in the emergency room before primary transluminal angioplasty in patients with acute myocardial infarction without compromising procedure success or clinical outcome.The early patency rates found in this study are consistent with other studies of abciximab use in acute myocardial infarction (GRAPE,TIMI 14).These studies suggest that glycoprotein IIb/Illa receptor blockers are unlikely to be effective monotherapy for restoring fufarct:-related artery patency and that future studies are needed to explore their adjunctive role with thrombolytic agents and early percutaneous revascularization.

Session New Studies Using Platelet ReceptorAntagonists \

Study: Sustained Platelet GP IIb/llla Blockade With Oral Orofiban: Interim Safety and Tolerability Results of the SOARStudy Presenter: P.C.Deedwanla,VA Medical Center/University of caIifomla San Francisco School of Medicine, Fresno, and G.D. searle &: Co., Skokie, m.

Results: The investigators of the SOARStudy (Safety of Orofiban in Acute Coronary Research) attempted to assess the safety and tolerability of orofiban, an oral platelet glycoprotein (GP) Ilb/Illa inhibitor, in patients with recent unstable angina or myocardial infarction. In this multicenter, double-blind, randomized, placebo-controlled study, 259 screened patients were prescribed aspirin (162 mg/day) and randomly assigned during hospitalization to placebo versus four doses of orofiban (30, 40,50 mg twice daily or 50 mg every day) for up to 3 months.The 4-week interim analysis of bleeding events was presented along with clinical and drug discontinuation data extending to >84 days. At the 4-week interim analysis, the incidence of withdrawal from bleeding events ranged from 1% to 5% in orofiban-treated patients. No deaths were reported and cardiac event rates were low in both placebo and active treatment arms. Eight bleeding events (one severe and seven mild) in the active treatment group resulted in withdrawals.The incidence of moderate or severe bleeds was low (0% to 2%) in actively treated patients. However, the incidence of insignificant and mild bleeding was significantly increased in the orofiban patients as epistaXis and bruising were the most commonly reported bleeding events. Bleeding rates were higher in patients over age 65 years. Overall bleeding event rates were dose related in the orofiban group.The highest rate of 34% was in the orofiban 50 mg/day group, whereas a rate of 24% was present in the orofiban 30 mg twice daily group. Placebo-treated patients had an 11% bleeding event rate. Despite the low rate of serious bleeding and clinical events, only 76% of placebo patients and 69% of orofiban patients completed the 4-week study on assigned therapy.

Interpretation: Combination therapy with aspirin and orofiban after myocardial infarction or unstable angina results in a low rate of serious bleeding events.A substantial number of patients are likely to have some bleeding events, and maintenance of drug therapy for even short duration may be difficult. Further phase m trials should address clinical outcomes.

Session Acute Myocardial Infarction: SHOCK and Ventricular Arrhythmias

Study: Lack of Progress in Cardiogenic Shock: Lessons From the GUSTOTrials

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Presenter: v. Menon, St. Luke's-Roosevelt Hospital Center, Columbia University Medical Center, NewYol'k, N.Y.

Results: This poster compared the incidence, procedure utilization, and outcomes of patients with cardiogenic shock enrolled in the GUSTO-m study (1995-97) and GUSTO-I study (1990-93).The analysis was restricted to enrolling countries that participated in both thrombolytic trials. 0vernll,695 (5.5%) GUSTO-m patients had cardiogenic shock compared with 2814 (7.2%) GUS'fO.I patients. GUSTO-m patients with cardiogenic shock were slightly older (69years vs 67 years) and more likely to have diabetes (23% vs 19%),hypertension (48% vs 44%),and anterior myocardial inf.lrction location (60% vs 51%).Despite similar rates of percutaneous transluminal coronary anglopJasty,coronary artery bypass grafting, and inttaaortic balloon pump use, the unadjusted mortality rate fur patients with acute myocardial infiudion and cardiogenic shock was higher in GUSTO-m (62.2% vs 54.3%,P 0.00(2). Reinfiudion (14% vs 100,p 0.012) and recurrent ischemia (35% vs 26%,p 0.‫סס‬OO1) were also more prevalent in the later GUSTO-m study. Mechanical ventilation, left heart catheterization, and right heart catheterization were usedsignificantly less often in the GUSTO-m cohort.

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Interpretation: Overall mortality from cardiogenic shock associated with myocardial infarction has not decreased in recent years in large thrombolytic trials. Increased age and anterior infilrct location likely contributed to increased GUSTo-m mortality rate. Future studies should address adjunctive therapies and better define the role of early mechanical revascu1arization in this high-risk patient group.

Session New Understandings ofAnticoagulation During Unstable Angina

Study: Heparin Dosing and Outcome inAcute Coronary Syndromes:The GUSTo-lIb Experience

Presenter: I.C. Gllchrist, Pennsylvania State University, Hershey, Pol.

Results: This presentation examined the relation of heparin dosing and 3().day outcome in patients with acute coronary syndromes.The population consisted of 5335 patients with unstable angina or myocardial infarction (ST elevation or depression) assigned to intravenous heparin therapy in the GUSTO-lIb triaI.AU

patients in this treatment group received a 5000 U bolus and 1000 U!hr initial infusion with later heparin dosing mandated by an algorithm guided by activated partial thromboplastin time (aPT!). Baseline characteristics, weight-adjusted heparin rate, and 12-hour aPIT were analyzed with respect to 3O-day death or reinfarction rate. An unadjusted relation that approached statistical significance existed between weight-indexed heparin rate and death (chi-square 0.3,p 0.054) and heparin rate and death plus reinfarction (chi-square 7.58,p = O.056).A nadir mortality rate was noted at a heparin dose of 14 U/kg/hr with higher death rates present at higher and lower doses. Weight-based heparin dose linearly predicted the 12-hour aP'IT in the study, and adjustment for 12-hour aP1T value resulted in a decreased association between heparin dose and outcome.

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Interpretation: This presentation confirms recent studies showing that intermediate doses of heparin (12 to 15 U/kg/hr) may be optimal for acute coronary syndromes. It also reinforces the benefits of weight-based heparin dosing and suggests the need for further studies to define those other patient characteristics that determine heparin consumption and influence anticoagulation efficacy.

Session NewApproaches to Myocardial Preservation inAcute Myocardial Infarction

Study: Results of Intracoronary Recombinant Human Vascular Endothelial Growth Factor (rhVEGF) AdministrationTrial Presenter: TIm D. Henry, Hennepin County Medical Center, Minneapolis, Minn. Results: Vascular endothelial growth factor (VEGF) is a heparin-binding growth factor that is secreted naturally by cells in response to ischemIa.VEGF acts through FIt-l and KDR receptors expressed on endothelial cells to promote endothelial growth and angiogenesis.Animal studies have suggested that increasing levels ofVEGF in ischemic myocardium promote local angiogenesis and improve myocardial perfusion. This study was a multicenter, open-label dose escalation trial designed to examine the safety and tolerability of Iatracoronary recombinantVEGF (rhVEGF) in human beings. Patients with stable exertional angina and areas of

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viable but underperfused myocardium who were not otherwise candidates for surgical or percutaneous revascularization were enrolled. Patients with diabetes, proliferative retinopathy, and a history of cancer were excluded. Patients received a 100minute infusion of rh VEGF in each coronary artery distribution at doses ranging from 0.005 to 0.167 mg/kg/min. Rest and exercise nuclear perfusion imaging (SPECO was performed at baseline and at 30 and 60 days after treatment. Fifteen patients were enrolled, of whom 87% were male, 40% had previous coronary artery bypass grafts, and 73% had previous percutaneous translummal coronary angioplasty. There was a dose-dependent decrease in systemic blood pressure during administration of rhVEGEAt the highest dose tested (0.167 rug/kg/min), patients had a mean decrease in systolic blood pressure (possibly caused by increased vascular permeability or vasodilatation) of 28 ± 8 mm Hg. Infusions of 0.050 mglkg/min resulted in less change in blood pressure. There were no serious clinical events or significant changes in patient status (blood chemistries, allergy, ophthalmologic vascular changes).Although the study was not designed to demonstrate efficacy, seven of 15 nuclear single-photon emission computed tomography scans improved after 60 days of follow-up. These seven patients subsequently underwent follow-up angiography, with five of seven showing overall angiographic improvement of collateral density.

Interpretation: Recombinant vascular endothelial growth factor appears to be well tolerated by human beings when given by intraeoronary infusion.There is a dosedependent decrease in blood pressure during infusion, with no severe side effects observed (at any of the doses tested) up to 6 months. Initial clinical results are promlsing with regard to angiogenesis, but further clinical studies are needed to confirm efficacy.

Session Clinical TrialsWith Antiplatelet Agents During Interventional Procedures

Study: safety of Readministration ofAbciximab: Interim Results of the ReoPro ReadministrationRegistry Presenter:James E.Tcheng, Duke University Medical Center, Durham, N.C. Results: Results from the first 256patients in the ReoPro Readministration Registry were presented.The registry is a phase IV effort desJgned to investigate potential adverse

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reactions associated with the readministration of the glycoprotein IIb/Illa inhibitor abciximab. Patients were included if they received a second, third, or greater dose of abciximab at least 6 days after an initial dose. Patients were monitored for clinical events after readministration of abciximab and had prereadministration and postreadministrtion human anti-chimeric antibody (HACA) titers determined. Clinical success was high after readministratio (95%). There was a low (3.5%) incidence of thrombocytopenia (<100,000) and a 0.8% incidence of profound thrombocytopenia «20,OOO).There were no documented cases of allergic reaction with abciximab readministration.A total of 16.9% of patients had new HACA antibodies develop with abciximab readministration, although this result did not appear to be related to adverse outcomes.

Interpretation: As the use of abciximab during percutaneous intervention increases, more patients will receive it more than once.This paper represents the largest current experience with readministration of abciximab.Abciximab readministration appears to be sate, without significant risk of allergic reaction.Readministration, like first administration, of abciximab is associated with a low incidence of thrombocytopenia. Results on the full 500 patients planned to be included in the ReoPro Readministration Registryshould be available by Fall 1998.

Special Session Late-Breaking Clinical Trials II

Study: Plasminogen Activator and Angioplasty Compatibility Trial (PACO Presenter: Allan Ross, MD,George Washington University Medical Center,Washington, D.C.

Results: The PACT trial evaluated the safety and efficacy of pretreatment with a short-aeting thrombolytic (rTPA) agent before angioplasty for myocar
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receive a second bolus dose of the study drug administered earlier (either rTPA or placebo). Patients were subsequently evaluated with angiograms with ventriculography at 7 days and symptom-limited exercise tolerance tests at 6 weeks. The mean time between onset of chest pain and the first bolus of study drug (placebo or rTPA) was 2.7 hours for both groups.The time from administration of study drug to arrival in the cath lab was approximately 50 minutes. For patients who were reperfused without angioplasty, the median time from study drug bolus to documented TIMI grade 3 flow was 51 minutes (the vessel had likely opened at some time before, but the precise time was not known.) In patients who required angioplasty (either as a primary or rescue intervention), the median time to reperfusion was 90 minutes. Of the placebo-treated patients receiving only aspirin and heparin, 14.8% had TIMI-3 flow without an intervention, and an additional 19% hadTIMI-2 flow. In the rTPA group, 32.8% had TIMI-3 flow without an intervention, and an additional 27.7% hadTIMI-2 flow. Technical success rates were similar (95%) for both groups.The proportion of patients with restoration ofTIMI-3 flow was also similar for both arms (79% vs 77%). The incidence of in-hospital adverse events was similar for both groups, induding need for transfusion (13% placebo, 13% rTPA),urgent revascularization (7.4% vs 7.4%), cerebrovascular accident (0.7% vs 0.7%), and inhospital mortality (3.0% vs 3.6%).The 3O-day mortality rate was also similar between the two groups (3.3% placebo, 3.6% rTPA).The incidence of recurrent ischemia was 13.5% in the placebo group compared with 18.5% in the rTPA arm (p 0.(9).

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The prespecitied efficacy end point for this trial was predischarge ejection fraction detennined by follow-up ventrlcuIograms, stratified by the method ofTIMI-3 flow restoration. Patients withTIMI-3 flow on arrival (from aspirin, heparin, and rTPA) left the hospital with an average ejection fraction of 62%.This was significantly higher than the ejection fraction of 58% for patients who required an angioplasty to restore TIMI-3 flow. The ejection fractions for patients with rescue angioplasty were not different from those who received primary angioplasty. For reference, patients who never achievedTIMI-3 flow had a discharge ejection fraction of 55%.

Uanitations included empiric choice of dose of thrombolytic agent and trial environment with ready access to cathlab.

Interpretation: The primary advantages of thrombolytic therapy are universal availability and speed of administration. Reperfusion rates are higher for primary angioplasty,but there is often a delay before percutaneous intervention can be performed. Previous trials of angioplasty after thrombolytic therapy (I1MI-2,TAMI-l, ECSG, SWIFI) principally examined the value of angioplasty for the patients with clinical reperfusion after thrombolytic therapy.The small SAM! study found high success rates with combined thrombolytic therapy and primary angioplasty but with elevated rates of bleeding.This trial suggests that treatment with thrombolytics can increase patency upon arrival to the cath lab and confirms that early patency may be assodated with improved ejection fraction. The technical success rate of angioplasty appeared unchanged by prior rTPA administration, but the study has limited power to establish equivalence.

Interventional Cardiology Special Session Late-Breaking Clinical Trials II

Study: Multicenter, RandomizedTrial ofAbdximab in Stenting and Comparison withAbciximab Plus Balloon (EPILOGStent)

Presenter: Eric J. Topol, Cleveland Clinic Foundation, Cleveland, Ohio Results: Glycoprotein (Gp) IIb/Illa receptor inhibitors have been previously shown to decrease the incidence of death and nonfatal myocardial infarction associated with percutaneous coronary revasculariZation by approximately 40% compared with placebo controls, but much less evidence exists for a reduction in target vessel revascularization. On the other hand, intracoronary stenting has not been shown to significantly reduce death or myocardial infarction despite a relative reduction in repeat revaseularization rates of approximately 25%.The EPISTENT (EPILOGStent) study was designed to test two hypotheses: that stenting and concurrent GP IIb/Illa blockade would reduce mortality rate and nonfatal myocardial infarction and that balloon angioplasty and GP IIb/Illa blockade would be safer than stenting alone. The trial enrolled 2399 patients with coronary anatomy amenable to percutaneous intervention and symptomatic angina from 56 sites betweenJuIy 1996 and September 1m.Exclusion criteria induded bleeding diathesis, recent stmke, or uncontrolled hypertension. Patients were randomly assJgned to receive stents alone (n = 8(9), stents

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with adjunctive abcixirnab therapy (n 794), or angiopJas.. ty with abcixirnab therapy (n 796).The two stent arms were double blinded. Concomitant heparin was given at 100 U/kg (goal activated clotting time 300) for the stentonly arm and 70 U/kg (goal activated clotting time 200) for the other two arms. Demographic characteristics, including age, sex,and incidence of diabetes, were similar in the three arms. Sixteen percent of the patients assigned to the angioplasty arm crossed over to intracoronary stenting, whereas approximately 5% of patients in the other two arms were unable to receive stents.

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For the combined outcome of death, myocardial infarction, and urgent revascularization at 30 days, the event rates were 10.8% for stent with placebo compared with 5.3% for stents with abciximab and 6.9% for angioplasty with abciximab.The 51% relative reduction between the two stent arms was highly significant (p < 0.001), as was the 36% relative reduction between stent with placebo and balloon angioplasty with abciximab (p < O.OO7).Theincidence of death and large (Q-wave or non-Q-wave with creatine kinase >1000) myocardial infarction at 30 days was 7.8% for patients receiving stents alone compared with 3.0% for stents with abciximab and 4.7% for the balloon angioplasty arm. Eightyfive percent of the reduction in infarctions was attributed to Q-wave or large non-Q-wave infarctions.The majority of the difference was seen early, with an incidence of death or nonfatal infarction at 24 hours of 9.3% for the stent with placebo group compared with 4.2% for stenting with abciximab and 5.2% for angioplasty with abciximab. The incidence of major bleeding events was low (stent with placebo, 2.2%;stent with abciximab, 1.5%;angloplasty with abciximab, 1.4%).There were no intracranial hemorrhages during the trial.The incidence of ischemic stroke was 0.1 % for the stent with placebo group, 0.4% for the stent with abciximab arm, and 0.3% for the angloplasty with abciximab group.

Interpretation: This is the largest stent versus balloon angioplasty trial performed to date, with a patient population nearly twice as large as the BENESTENT n trial; plus, it enroUed a broad population of patients. Compared with previous percutaneous intervention trials of abciximab, the reduction of death and myocardial infarction from GP IIb/IIIa blockade appears to be device independent. Stenting with abciximab appears to be the strategy of choice in suitable patients.An economic comparison of the treatment strategies used by EPILOG-Stent wiD be available by August 1998.An

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angiographic substudy with angiographic follow-up is ongoing, with planned initial results in late 1998.

Special Session Late-Breaking Clinical Trials II

Study: Primary Angioplasty in Myocardial Infarctlon Trial (STENT·PAM!) Presenter: Cindy L. Grines,William Beaumont Hospital, Royal Oak, Mich.

Results: Compared with thrombolytic therapy, primary angioplasty has been shown to have higher initial patency rates and a lower incidence of death, recurrent infarction, and stroke.The primary hypothesis of stent-PAMI was that stenting would produce increased luminal diameters compared with primary angloplasty, decrease inhospital ischemia, and decrease the incidence of anglographic restenosis.The primary end point was a reduction in combined death, recurrent infarction, disabling stroke, and target vessel revascularization at 6 months.The trial was designed for a 90% power to detect a reduction in the primary end point from 30% to 20%. The investigators obtained consent from 1457 patients with acute myocardial in&rction ofless than 12 hours' duration. Patients with cardiogenic shock, prior thrombolytlc therapy; or contralndicatlons to aspirin, tidopidine, or heparin were excluded. Nine hundred patients were found e1lgible for randomization and received either a heparinized Palmaz-8chatz stent (n 452) or primary angioplasty without intraeoronary stenting (n 448). Notably,67 patients in the primary angioplasty group (15.1 %) crossed over to intraeoronary stenting. In the stent arm, 1.3%of patients did not have stent placement attempted because of lack of available product or technical concerns, and an additional 1.3% had fililed stent deployment.

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Tune-to-treatment was not significantly different in the two randomized arms (mean time from emergency room to first balloon inflation was 135 minutes for the stent group and 138 minutes for the angioplasty group).Adjunctive ticiopidi'ne therapy was used in 93% of the stent patients and 87% of the primary angioplasty group.Abciximab was used in 5.6% of the patients receiving stents and 4.5% of the angioplasty arm.The investigators recommended that stent patients with optimal stent results (<10% residual stenosis and Thrombolysis in Myocardial Infarction grade 3 flow) have sheaths removed after 6 hours and

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receive no further heparin therapy. By protocol, the stent group received significantly less postprocedure heparin (36% vs 77%,P 0.(01).

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Acute angiographic results showed no significant difference in preprocedure minimum lumen diameter (0.38 stent vs 0.37 percutaneous trans1uminal coronary angloplasty [PI'CA)) but a significantly larger postprocedure minimum lumen diameter (2.55 stent vs 2.11 PTCA,p O.OOl).There was no significant difference in overall inhospital ischemic events (2.9% stent vs 4.7% PTCA,p O.l7).There was a significant reduction in ischemia requiring target vessel revascularization at 30 days (0.9% stent, 3.5% PTCA,p 0.006). However, at 30 days, there was no significant difference in death (3.5% stent, 1.8% PTCA,p 0.15), reinfarction (0.4% stent, 1.1% PTCA,p 0.29), dJsabling stroke (0.2% stent,O% PTCA) or the combined end point (4.2% stent, 5.4% PTCA,p 0.54).

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Interpretation: Although stenting produced larger vessel diameters, use of the heparin-coated P.11maz-Schatz stent did not influence the composite end point of death, reinfarction, or ischemic total vascular resistance at 1 month. Previous, smaller trials of intraeoronary stenting (Zwolle, PASTA) sugested a greater clinical benefit for primary stenting at 30 days than seen in stent-PAMI.The low event rate in the angioplasty arm was unexpected but perhaps attributable to the 15.1% crossover rate to stentlog in the angioplasty arm.Analysis of the primary end point (6-month combined clinical outcomes) and (). month angiographic results is in progress, and a I-year economic outcome analysis is planned.

Session Stent Restenosis: Mechanisms, Prevention,Treatment

Study: Influence of Routine Angiographic Follow-Up on Clinical Resten08is Outcome in theASCENTTrial Presenter: Donald E.Cutlip, Beth Israel Deaconess Medical Center, Boston, Mass.

Results: To evaluate whether routine angiographic fo1low-up after stent implantation has any effect on rates of target lesion revascularization (TLIt), 538 patients enrolled in the ASCENT trial who were scheduled to underRo protocol angiography after stent placement were compared with the remaining 502 patients who had only clinical follow-up. Baseline characteristics of the two groupsw~not significantly different. 0verall1'LR was performed in 15% of patients receiving protocol angiography versus only 9.2% of patients receiving cJini.

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cal follow-up (p 0.(04). Concomitant ischemia in the protocol angiography group could not account for the differences in TI.R. rates because reevaluation of the data based on ischemia before revascularization (87% of patients in the angiographic group) only partially corrects the differences (13% vs 9.2%,P 0.049). In addition, there were no significant differences in actual percentage of stenosis between the groups.Adjudication of TI.R. could not correct the differences either{12.1% vs 8%,P 0.031). Independent predictors of1'LR included male sex,diabetes, final minimum lumen diameter, vessel diameter, lesion length, left anterior descending artery lesions and, as expected, angiographic follow-up.

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Interpretation: Overall, routine angiographic follow-up after successful stent placement appears to increase rates of1'LR and often reflects revascularization in patients without clinical evidence of ischemia (13% of the anglographically followed patients in this study). In addition, protocol angiography during trials may increase estimates of clinical restenosis with TI.R. of otherwise clinically insignificant 50% to 70% lesions.

SpecialSession Late-Breaking ClinicalTrials II

Study: Total Occlusion Study of Canada (fOSCA) Presenter: Christopher E.Buller,Vancouver General Hospital,Vancouver, British Columbia, Canada

Results: TheTOSCA study was a randomized trial of heparin-bonded Palmaz-8chatz stents versus balloon angioplasty in symptomatic, nonacute, coronary occlusions.A total of 410 patients were randomly assigned to Palmaz-schatz heparin
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and I-year clinical outcomes.The primary end point was failure of sustained patency, defined as TIMI flow <3 at or before 6 months accompanied by significant restenosis in the vessel. Secondary end points included a 6-month quantitative angiographic minimum lumen diameter measure, a I-year target vessel revascularization end point, and a I-year combined composite cardiovascular endpoint. Changes in global and segmental left ventricular function were also analyzed. Buller presented the 6month primary angiographic end points, as well as 6month interim clinical data. A total of 208 patients were randomly assigned to primary angloplasty, and 202 patients were randomly assigned to the stent arm.There was no significant difference in age, ejection fraction, incidence of diabetes, history of prior myocardial tnfarcnon, or length of stay in the two groups.The average occlusion age was approximately 10 weeks, and 60% of patients hadTIMI 0 flow at baseline. Approximately 40% of patients had a left anterior descending target vessel, 40% had right coronary lesions, and 20% had circumflex stenoses.The investigators estimated baseline lesion length using prerandomization operator estimates based on contrast penetration and collateral filling.The core laboratory measured a working segment length, which was the length of the segment aetualIy treated during the procedure. Operator estimates of segment lengths averaged 20 mm, whereas core lab measurements were higher at 35 mm.As a result of the long lesions encountered in this trial, the majority of patients required multiple stents, and 25% of patients required 3 or more stents to obtain a satisfactory result. In the angiopIasty arm, 20 (l0%) patients crossed over to stenting, whereas eight (4%) patients in the stent arm were unable to have devices placed.Abciximab, which was not controlled, was used in 3% of both groups. Three-hundred ninety two patients (200 percutaneous transluminal coronary angioplasty [PrCAl, 192 stent) completed 6-month angiographic follow-up. In the PrCA arm, 22 patients hadTIMI-G flow, five patients had TIMI-I flow,and 12 patients hadTIMI·2 flow for a total failed patency rate of 19.5%. In the stent arm,I3 patients had TIMI-G flow, three patients hadTIMI-I flow, and five patients hadTIMI·2 flow for a total failed patency rate of 10.9%.The difference between the two arms was significant by Fisher's exact test (p = 0.024). Quantitative angiographic results showed significant (p < 0.01) differences in late loss, final minimal lumen diameter, resIdual stenosis, and percent restenosis (70% PrCA vs 56% stent).A total of 13.9% of patients had target ves-

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sel revascularization at 6 months in the angiopIasty group compared with 7.4% in the stented group (p = 0.038). Mortality rate at 6 months was the same in both groups (0.5%).The incidence of small periprocedural Infarenon was higher in the stent group (5.4% vs 1.0% PrCA).The incidence of all other infarcts was low in both groups (4.7% stent vs 2.0% PrCA).The composite end point of death, any myocardial infurction, and any revascularization was 20% in the angiopIasty group and 22.3% in the stented group (p = not significant).

Interpretation: Primary stenting resulted in improved 6month patency,targer 6-month lesion diameters, and a decreased need for target vessel revascularization. Buller preliminarily recommended primary stenting for qualifying lesions. One-year clinical end points are forthcoming.

Session AngiopIasty and Stenting inAcute Myocardial In&rction

Study: One Year SurvivalAmong Patients With Myocardial In&rction Complicated by Cardiogenic Shock Alive at 30 Days and the Impact of Early Revascularization: Results from GUSTO-I Presenter: Peter B.Berger, Mayo Clinic and Foundation, Rochester, Minn.

Results: In patients who are treated for acute myocardial inf.ttrtion (AMI) complicated by cardiogenic shock, early catheterization (within 24 hours) hasbeen shown to be an independent predictor of improved 3O-day survival (hazard ratio O.4).To evaluate long-term benefits of early and aggressive revascularization in patients seen withAM! complicated by shock, I-year outcomes of 1321 patients from the GUSTO-I population with shock who survived 30 days were evaluated based on whether they had (n 528) or had not (n 793) received revascularization within the first 30 days.Among 3O-day survivors who received revascularization, I-year survival was improved compared with those who did not undergo revascularization (92% vs 88%,p 0.003). Survival curves continued to diverge at I year, and, after regression analysis, revascularization within 30 days remained as an independent predictor of survival (hazard ratio 0.6, 0.4-0.9,p 0.007).

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Interpretation: Among patients withAM! complicated by shock who survive 30 days, early invasive strategy and revascularization in appropriate patients appear to result in continued and long-term survival benefits up to 1 year. Despite the persistent possibility of bias in favor of revascularization, this study, along with previous studies of

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short-term survival, supports an aggressive approach to patients who are seen for AMI complicated by cardiagenic shock.

Secondary Prevention Special Session New Observations From Recent Clinical Trials

Study: Azithromycin in CoronaryArtery Disease Elimination of Myocardial Infection with ChJarnydia(ACADEMIC) Presenters: Jeffrey L.Anderson andJoseph B.Muhlestein, University of Utah School of Medicine, Salt Lake City,Utah Results: A number of organisms have been implicated in the development of atheroma and the inflammatory cornponent of vascular injury, including Helicobacter pylori, cytomegalovirus, and Chlamydia pneumoniae. However, there hasbeen no proof of causality in human beings. Reportsby Gupta et al. 1 and Gurfinkel et al.2 have suggested that macrolide antibiotic therapy may reduce the incidence of cardiovascular events.ACADEMIC was a doubleblind, randomized, secondary prevention trial of azithromycin in patients with documented, symptomatic coronary disease and immunoglobulin G (IgG) titers of at least 1:16 for chlamydia. Randomized therapies included oral azithromycin 500 mg daily for 3 days, then once weekly for 3 months,or matching placebo.The specific lab0ratory hypotheses were that azithromycin would decrease levelsof c-reactive protein (CRP), interleukin (IL)6, and tumor necrosis f.lctor (I'NF) at 3 months (the primary end point) and at 6 months.Another secondary end point was a decrease in antkhlamydial IgG titers at 6 months.The clinical hypothesis was that azithromycin would decrease the incidence of composite events (cardiovascular death, non&tal infMction, resuscitated cardiac arrest, hospitalization for unstable angina, unplanned revascuJarization, and nonfatal stroke) at 6 months and 2 years (the primary c1inical end paint).The study was powered to detect a large decrease in events from 28% to 14%.Patients with previous myocanUal inWction or angiographic evidence of coronary disease were included.The study excluded patients with concurrent macrolide use or intolerance, New York Heart.A88ociation class ill or IV heart f.lilure, ejection fraction <25%, myocanUal inmrction within 5 days, bypass swgery within 1 month, percutaneous intervention within 3 months, or patients scheduled for future bypass S\J1'8CfY or coronary interventions.

June 1998

assigned. In the randomized population, 88% were male and 61% had had previous myocardial infarctions.There was no difference in baseline CRP, IL-1, IL-6,orTNF levels in the patients receiving azithromycin (n 150) or placebo (n 152).At 6 months, patients in the placebo group had higher changes in CRP levels (0.01 azithromycin, 0.15 placebo). Similarly, circulating IL-6levels were significantly blunted by azithromycin at 6 months (mean change 0.55 azithromycin, 1.8 placebo). No differences were found between treatment groups for IL-1 and TNF inflammatory markers.The prespecified primary laboratory end point, a combined analysis of all four markers at 3 months, was not statistically different between the two treatment groups.There were no significant changes in serum anti-chlamydial IgG or 19A titers during the ~ month course of the study.

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In a ~month interim clinical analysis, there was no difference in the incidence of combined cardiovascular clinical events (azithromycin 9 of 150,placebo 7 of 152).The individual study patients will remain blinded until the primary 2-year clinical events can be ascertained. During the 3-month period of study drug administration, 21 % of patients receiving azithromycin and 9% of patients receiving placebo had adverse reactions, primarily nausea and diarrhea. Not surprisingly, there were fewer clinical infections requiring antibiotic therapy in the azithromycin arm.

Interpretation: Although there was no significant difference between treatment arms at 3 months, there was a statistically significant stabilization of CRP and IL-6by 6 months.Although the authors cited intriguing pilot studies, expressed enthusiasm for the trend towards stabilized CRP and IL-6,and called for longer-term studies, it remains to be seen whether azithromycin produces a difference in clinical events.The marked reductions in clinical events reported in two earlier, smaller studies appear to be overly optimistic.

References 1. Gupta S, leatham EW, Carrington D, Mendall MA, KaskiJC, Camm

AJ.

Elevated Chlamydia pneumoniae antibodies, cardiovascular

events, and azithromycin in male survivorsof myocardial Infarction. Circulation 1997;96:404-7. 2. Gurfinkel E, Bozovlch G, Daroca A, Beck E, Mautner B. Randomized trial of roxithromycln in non-Q-wave coronary syndromes: ROXIS Pilot Study. lancet 1997;350:404-7.

Surgery A total of 442 patients were screened, and 302 of them hadpositive chlamydia titers and were rmdomJy

Sp.cial Session New Observations From Recent Clinical Trials

American HeartJournal Volume 135,Number6, Part 1

Study: Long-Term Follow-Up of the Post-CoronaryArtery Bypass GraftTrial (POST-CABG) Presenter: Genell L,Knatterud, Maryland Medical Research Institute, Baltimore;Yves D. Rosenberg, National Heart, Lung, and Blood Institute, Bethesda, Md.

Results: The POST-CABG trial randomly assigned 1351 patients with coronary artery bypass grafting to (1) aggressive versus moderate LDLcholesterol lowering with lovastatin and (2) low-dose warfarin versus placebo in a 2 by 2 factorial design. 1 Patients had baseline LDLcholesterol levels between 130 and 175 mg/dl and at least one patent vein graft documented by angiography.A total of 337 patients received "aggressive" highdose lovastatin (40 to 80 mg) and 1 to 4 mg warfarin (to an international normalized ratio of <2.0); 339 patients received high-dose lovastatin and placebo; 337 patients received "moderate" low-dose lovastatin (2.5 to 5 mg) and warfarin (to an international normalized ratio of <2.0); and 338 patients received low-dose lovastatin and placebo.The primary end points were angiographic.A 31% reduction in late obstructive changes and a 29% reduction in revascularizationl were observed in favor of the aggressive versus the moderate. No significant difference was observed between the warfarin and placebo groups. The investigators reported preliminary results from extended follow-up interviews conducted between September 1997 and March 1998.The average duration of follow-up was approximately 7.5 years, an extension of more than 3 years beyond the original report.The objectives were to examine the long-term effects of therapeutic strategies used in the trial and to determine the predictive value of the angiographic findings for subsequent events. Patients were contacted by telephone to determine the occurrence of cardiovascular events (death, myocardial infarction, angioplasty, or repeat coronary artery bypass graft). Medical records were obtained for further review.

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(AW), 18% (AP), 23% (MW) and 25% (MP).The incidence of one or more of the above events was 25% (AW),32% (AP), 34% (MW), and 41% (MP). Likelihood ratios calculated with a Cox proportional hazardsmodel showed no significant interaction between LDL-Iowering and anticoagulation strategies.Therefore the effects of the lipid-lowering strategies were evaluated by pooling the arms with respect to warfarin versus placebo. Similarly,the effect of warfarin was evaluated by pooling the lipid-lowering strategies.There was no difference in the incidence of death and nonfatal Ml for either of the lipid-lowering strategies in the extended follow-up period, but there was a significant difference in the incidence of revascularization (p O.ool).A significant difference in the occurrence of death or M1 emerged in the warfarin vs placebo groups (p 0.001), but no difference was observed in repeat revascularization.

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Interpretation: The previously reported trends observed during the initial follow-up period of 4.3 years became statistically significant during the extended follow-up period.Aggressive lowering of LDLcholesterol levels to below 100 mg/dl is associated with a lower incidence of repeat revascularization. Low-dose warfarin may reduce the incidence of death or myocardial infarction in CABG patients, but this surprising finding needs to be confirmed by larger studies.

Reference 1. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levelsand low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N EnglJ Med 1997;336: 153-62.

Valvular and Congenital Heart Di.ea.. Special Session New Observations From Recent Clinical Trials

Study: Prevalence ofValvularAbnormalities in Patients Exposed to Dexfenflwamine; Results of a Randomized

The mortality rates were 11% for the aggressive warfarin (AW) group, 13% for the aggressive placebo (AP) group, 10% for the moderate warfarin (MW)1VOuP,and 19% for the moderate placebo (MP) group.The incidence of myocardial infarction was 9% (AW), 11% (AP), 10% (MW), and 14% (MP), respectively, in the four arms.The incidence of combined death or myocardial infarction was 18% in both warfarin arms,21% in theAP arm,and 28% in the MP arm.The incidence of revascularization (angioplasty or repeat coronary artery bypass graft) was 16%

Placebo Controlled Trial

Presenter: Neil).Weissman, Georgetown University Medical center,Washington, D.C.

Results: Previous reports have suggested the incidence of valvular abnormalities to be as high as 32.8% in patients treated with the anorexic drugs phentermine, fenfluramine, and dexfenfluramine. 1,2 On the basts of these reports, fenflwamine and dcxfenfluramine were

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voluntarily withdrawn from the market. During 1997, a safety and efficacy trial of dexfenfluramine was in progress, with patients randomly assigned to either 15 mg dexfenfluramine twice daily, 30 mg daily of an investigational sustained-release dexfenfluramine, or placebo control. Of 1598 patients screened, 1212 patients had been equally randomly assigned to the three treatment arms (404 per arm).Approximately 80% of the patients were female and 80% were white.The safety and efficacy trial was stopped after patients had received their assigned therapy for a median of 75 or 77 days. Patients were offered echocardiography, and 1072 echocardiograms were completed. I.eaflet mobility was evaluated as well as the presence of aortic, pulmonic, tricuspid, and mitr.ll valvular regurgitation. Echocardiograms were adjudicated by reviewers blinded to treatment assignment. The investigators used the Food & Drug Administration case definition (any mitral regurgitation of at least moderate grade, or any aortic insufficiency of at least mild grade) to detect significant regurgitant lesions.The incidence of significant aortic insufficiency was 5.0% in the dexfenfluramine group, 5.8% in the sustainedrelease dexfenfluramine group, and 3.6% in the placebo group. The incidence of significant mitral regurgitation was 1.7% in the dexfenfluramine group, 1.8% in the sustainedrelease dexfenfluramine group, and 1.2% in the placebo group.The incidence of either regurgitant lesion was 6.5% in the dexfenfluramine group, 7.3% in the dexfenfluramine SR group, and 4.5% in the placebo group. The incidence of any type of aortic insufficiency was 17% in the dexfenfluramine group, 17% in the sustainedrelease dexfenfluramine arm, and 12% in the placebo group. Mitr.ll regurgitation of any severity occurred in 61 % of the dexfenfluramine group, 61 % of the sustainedrelease dexfenfluramine group, and 54% of the placebo group (p = 0.037).The investigators attributed this difference to a higher prevalence of"physiologic" and mild regurgitation.There was no statistically significant difference in mean pulmonary arterial pressures in the 331 patients with sufficient tricuspid regurgitation to calculate this measurement.

Interpretation: The study is limited by the short exp0sure of patients to dexfenfluramine, limited statistical power, and the lack of pretreatment echocardiograms. However, the withdrawal of dexfenfluramine obviates further studies. Using the patients enrolled in this study, investigators showed no significant increase in the prevalence of significant aortic or mitr.ll insufficiency (by Food & DrugAdministration criteria), with the analysis com-

paring each of the treatment arms to placebo and not examining the two treatment arms combined. Preliminary reports- suggest that the incidence of valvulopathy may be higher in patients exposed to fenfluramine or dexfenfluramine for longer than 6 months.The higher prevalence of"physiologic" and mild regurgitation may reflect a.forme fruste of clinically significant valvulopathy. It is also possible that the prevalence of regurgitant lesions may be lower than in previous reports.The investigators correctly cautioned that the study results should not preclude appropriate evaluation of patients exposed to anorectic drugs of this class.

References 1. Connolly HM, Crary Il. McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et 01. Valvular heartdisease associated with fenfluramine-phentermine. N EnglJ Med 1997;337:581-8. 2. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health Recommendations, November 1997. MMWR 1997;46: 1061-6.

Congestive Heart Failure Session Late-Breaking ClinicalTrialsI: Heart Failure andArrhythmia

Study: Assessment ofTreatment with Lisinopril and Survival (ATLAS)

Presenter: Milton Packer, Columbia University College of Physicians and Surgeons, NewYork, N.Y.

Results: The ATLAS trial was designed to determine whether there was a difference in outcome between using high and low doses of the angiotensin converting enzyme (ACE) inhibitor lisinopril.The trial took place at 287 centers in 19 countries.The rationale for the study was that although ACEinhibitors are the only agent known to improve survival in congestive heart failure (CHF), they are frequently prescribed at doses much lower than the doses used in the trials showing a benefit of this drug class. Patients with moderate to severe CHF, NewYork HeartAssociation class mor IV (and some class n if hospitalized for CHF) were studied. Patients were excluded for renal dysfunction and hypotension, but not if they were alreadyon anACE inhibitor. Three thousand five hundred patients were screened,400 of whom were not receiving anACE inhibitor.All patients took open-label Hsinopril at 12.; to 15 mg over a 2-week period, Patients not taking anACE inhibitor were started on a dose of 2.; to 5 mg initiallyand then titrated to the nm-in

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dose of 12.5 to 15 mg after 2 weeks. Ninety-five percent of the patients participating in the run-in phase of the trial tolerated the doseand were randomly assigned to either lowdose (n =15(8) or high-dose (n =1596) lisinopril. Dosing was set at levels to reflect either the lower doses most patients receive, 2.5 to 5 mg of lisinopril per day,or the higher doses found efficacious in clinical trials, 32.5 to 35 mg per day.Ninety percent of the patients randomly assigned to the high-dose arm of the trial tolerated 35 mg per day.At the end of the trial, the actual difference in ACEinhibitor dose was only 19 mg because of the withdrawal of the study medication by some physicians and the subsequent prescription of open-label ACEinhibitor. Patients were followed-up for 3.5 years. The primary outcome of the trial was all-cause mortality. A total of 717 (44.9%) patients taking low-dose lisinopril died compared with 660 (42.5%) patients taking highdose (odds ratio [ORj 0.92,95% confidence interval [OJ 0.82 to 1.03,p =0.128).There was no sjgnificant difference in cardiovascular mortality (642 vs 583 deaths, OR 0.9,95% CI 0.81 to 1.01,p 0.073).The secondary outcome having priority over other secondary outcomes was all-cause hospitalization and mortality.The patients taking high-dose lisinopril were significantly less likely to have this result than were patients taking low-dose lisinopril (1339 vs 1251, or 83.9% vs 79.5%;OR 0.88, 95% CI 0.82 to O.96,p 0.002).This finding remained significant when looking at all-cause mortality and canliovascular hospitalization or CHF hospitalizations.There was also a significant difference in recurrent hospitalizations for either all causes and cardiovascular causes, or due to CHF with patients taking high-dose lisinopril having fewer rehospitalizations.

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The misconception that there is a higher incidence of side effects with high-dose ACEinhibition was considered by the ATLAS investigators to be a major cause of physicians' prescribing low doses. However, there was no meaningful difference in the side-effect profile of low- versus high-dose lisinopril. No important difference was seen for episodes of dizziness, hypotension, decreasing renal function, hyperkalemia, or hypokalemia. In fact, low-dose patients had an insignificantly higher incidence of cough than high-dose patients, and more patients were withdrawn from low-dose lisinopril than high-dose lisinopril. The investigators remarked that increasing the dose from low to high resulted in 50% of the effect ofACE inhibitors.Thus a physician has as much reason to

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increase the dose as to start an ACEinhibitor. In the United States, the increase in ACEinhibitor dosing to high dose would translate into 250,000 preventable hospitalizations each year and the avoidance of 100,000 hospitalizations and deaths.

Session Late-Breaking Clinical Trials I:Heart Failure and Arrhythmia

Study: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Presenters: SalimYusuf,McMaster University,Hamilton, Ontario, Canada and Jean-Lucien Roluleau, Montreal Heart Institute, Montreal, Quebec, Canada Results: This pilot study evaluated the effect of candesartan, an angiotensin-IT receptor antagonist, either alone or in combination with an angiotensin-converting enzyme (ACE)inhibitor versusACE inhibition alone.The primary outcome was 6minute walk. Other outcomes were ventricular function, neurohormones, and quality of life (QOL).The inclusion criteria included left ventricular ejection fraction <40%, NewYork HeartAssociation (NYHA) class IT or more, and tolerance of a brief openlabel, run-in period with both candesartan and enalapril, anACE inhibitor. Sixty-fivepercent of the patients were in NYHAclass IT, whereas fewer than 5% of the patients were in class Iv. A total of 769 patients were randomly assigned to one of the following six arms: three doses of candesartan (4,8, or 16 mg per day), two doses of candesartan and enalapril (4 or 8 mg candesartan and 20 mg enalapril per day), or 20 mg of enalapril. Patients were evaluated at 18 weeks and 43 weeks. There was no change in the primary outcome of the 6 minute walk with combination therapy, but candesartan and enalapril separately were significantly different versus combination therapy at 18 weeks but were similar at 43 weeks.At 18 weeks, there was no significant change in ejection fraction among groups. However, at 43 weeks, the group with combination therapy had a significant increase in ejection fraction. Combination therapy also significantly attenuated left ventricular dilation versus either enalapril or candesartan alone.The same trend was seen with dIastolic volume. Candesartan alone significantly increased angiotensin IT levels (p < 0.(01). Enalapril caused a drop in angiotensin IT levels. Combination therapy blunted the

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increase in angiotensin II levels found with candesartan. Combination therapy initially decreased aldosterone levels significantly (p < 0.01), but there was an increase over a 43-week period. Both atrial natriuretic factor and BNP were decreased with combination therapy compared with the other arms.Approximately 90% of the patients continued their medications, and this rate was similar among all groups. Hypotensive symptoms were similar among all groups at approximately 1%. There were no significant differences in the clinical outcomes of death, CHF hospitalization, or any hospitalization between candesartan alone, enalapril alone, or candesartan and enalapril together. The second part of the presentation described the results of the metoprolol CR substudy. Four hundred twenty-six patients who had completed 18 weeks of candesartan and had no contraindication to b-blockers participated in this study.The same outcomes as the main trial were used in this substudy, which compared 200 mg of metoprolol CR with placebo over a 24-week period. Ninety percent continued blinded medication. Eighty percent tolerated the full 200 mg dose. 1here was no significant difference in the 6minute walk or systolic blood pressure, but heart rate was significantly lower in patients taking metoprolo1.There was a significant decrease in angiotensin II lems, left ventricular end-systolic volume, and attenuation of the increase in left ventricular end-diastolic volume in patients taking metoprolol. Ejection fraction increased significantly with metoprolol.1here was no effect on QOL, exercise tolerance, or functional class. There was a significant increase in CHF hospitalizations that predominantly took place early. Total hospitalizations were similar.There was a trend toward a reduction in mortality rate, so that there was no difference in the composite of death or hospitalization for heart failure.

Session OUtcome Measures in Heart Failure

Study: Reduced Hospitalizations and Health Care Costs by an Interactive Home Monitoring Program for Heart Failure Patients Presenter: PaulA. Heidenreich, Stanford University, Stanford, Calif. The use of a multidisciplinary program, including patient education, monitoring, and physician education, was eval-

American Hearl Journal June 1998

uated in this study.The unusual feature of this program

was the use of an interactive computer system that patients would dial into and enter their data. This study was sponsored and the data collected by the maker of the computer, HillFE Inc. Dr.Heidenreich consulted for the final analysis of the data. A total of 15,000 patients were screened at 85 offices of physicians participating in a healthcare network. From this patient list, physicians selected 600 patients in New York Heart Association class II-Iv. Of the 600 patients, 128 were identified as having more than $50 of claims for heart failure procedures in 1994 or 1995.Twenty-six of the 128 patients were enrolled. In addition, 42 patients referred to the program were enrolled. Each patient received a digital scale and auto-blood pressure cuff.After receiving 2 to 3 hours of training from a nurse, patients were asked to call the computer daily and enter vital signs and symptoms.Weekly mailings of patient education material on heart failure were sent to the patients, and weekly phone calls from a clinical nurse were made to review the materials and answer any questions. Physicians set the parameters for vital sign alarms in the computer. Once an alarm sounded, nurses confirmed the alarm and sent a fax to the physicians describing the alarm.

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The study inciuded a control group (n 86) matched to the intervention group on 1995 claims.The intervention group was monitored for 12 ± 3 months. During this time, there were'294 physician notifications because of abnormal symptoms or signs in 53 patients.Thirty-three patients in the intervention group accounted for 57 admissions. seventy-five percent of the physicians were notified 14 days before an admission for heart failure; 17% were notified 14 days before an admission for non-heart failure causes. For the intervention group, baseline characteristics were the following: 73 ± 13 years average age, 55% male, 25% widowed, 32% diabetic, 44% with previous myocardial infarction or revascularization, 27% with sodium <136, and 24% with creatlnlne level >24%.Fifty-five percent of the intervention patients had at least moderate systolic dysfunction. Seventy-five percent were taking angiotensinconverting enzyme inhibitors, 57% were taking digoxin, and 58% were taking diuretics.The average number of medications taken was 8 ± 3. No clinical or baseline characteristics were provided for the control population. The outcome of the physician notification system was

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tracked using the munber of notifications, the percentage of patients with cardiac medication changes within 3 days of notification, and the percentage of patients with a resolution of complaint within 3 weeks. Of 294 total physician notifications, only 13% resulted in a medication change within 3 days and only 9% had resolution within 3 weeks according to patient reports. When broken down by specific complaints, the overall trend was maintained. For example, there were 46 complaints of weight gain based on the parameters set by the physician.Yet only 20% of the notifications resulted in a medication change, and only 11% of the patients had any action taken regarding their complaint within 3 weeks. The primary outcome was differences in total claims per person per year from baseline to the end of the intervention.The average number of claims per year during the intervention was significantly lower in the enrolled patients.The cost of the program was estimated at $200 per patient per month. For the analysis of resource utilization, only 43 of the enrolled patients were used because they were the only ones with claims data going back far enough for the analysis. The enrolled and control patients were well matched on sex and age. In addition, baseline claims for 1995 were well matched for total claims amount ($8500 ± 13,000 vs $9200 ± 15,000,p 0.8), number of claims per year (7.7 ± 1.9 for both), admissions per year, and hospital days per year. During the intervention period, there was a significant difference in total claims amount ($7,400 ± 11,700 vs $18,800 ± 34,000,p 0.04). In addition, there was a strong trend toward decreasing the number of claims per year (7.7 ± 1.6 vs 8.4 ± 1.9,p 0.06), admissions per year, and hospital days per year. Forty percent of the patients had no charges during the intervention period, and approximately 5% had costs more than $100,000. No explanation was provided for the sharp increase in resource use for the control group during the intervention period.

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An average of 82% ± 1()oA, of the enrolled patients survived for the 12 months of the intervention. QOL measurements remained stable. Eighty-five percent of the patients were compliant with daily phone calls.

Interpretation: The study had a number of limitations.The investigators noted that the patients were not randomly assigned, and control patients were not matched by clinical characteristics. In addition, the involvement of the company sponsoring the program in the protocol development and patient selection may call into question the outcomes of the trial. However, the study provides encouraging information regarding the use of computer technolo-

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gy within a multidisciplinary program based in the community.The implementation of such programs may lead to reduction in hospital admissions and medical claims.

Session Amyloid and Inflammatory Myocardiopathy

Study: Echocardiographic Identification of Cardiac Amyloidosis Patients Capable of Undergoing Intensive Treatment With Intravenous MelphalanTherapy Presenter: LisaA. Mendes, Boston University Medical Center, Boston, Mass. Results: Primary amyloidosis is characterized by protein deposition.This disease carries a poor prognosis, especially when involving the heart.The median survival is 6 months. Disease remission is possible with aggressive therapy with intravenous (IV) melphalan followed by autologous stem cell transplantation.This therapy has a number of side effects, the most pronounced of which are increased fluid retention and increased risk of infection.This study was undertaken to determine if patients with cardiac involvement could tolerate N melphalan and to determine the echocardiographic features that would predict which patients would tolerate the therapy. Sixty-four consecutive patients with biopsy-proven primary amyloidosis who underwent echocardiograms before therapy with N melphalan were included in the study. Twenty-nine of the 64 patients had cardiac involvement defined as any septal wall thickness>11 rom unexplained by high blood pressure or valvular disease. Patients were treated with granulocyte colony-stimulating factor for 5 to 6 days before undergoing stem cell harvest. Patients then received N melphalan with stem cell infusion after 72 hours. Of the 11 patients who died during the initial therapy, eight had cardiac involvement (p = O.07).After 1 year, 15 of 28 patients with cardiac involvement had survived versus 30 of 36 patients without cardiac disease (p 0.2). Eight of 28 patients with cardiac involvement died while undergoing treatment. Patients dying during therapy had no significant difference in age, sex, or NewYork Heart Association classification. However, they did have a significant increase in septal wall thickness (14.8 ± 1.7 vs 13.1 ± 1.3 mm,p = 0.007), posterior wall thickness (14.0 ± 1.6 vs 12.6 ± 0.8,p = 0.004), and ventricular wall fractional shortening (25 ± 9% vs 34 ± 11 %,P = 0.06).

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significant increase in the likelihood of death during the peri-thempy period. These patients could not be distinguished on clinical grounds but did have significantly increased ventricular wall thickness and lower fractional shortening.The difference in the incidence of death between patients with cardiac amyloidosis and those free of cardiac involvement was similar at 1 year.Patients with cardiac involvement should not be excluded from IV melphalan. Future studies need to refine the methods used to identify patients with cardiacamyloid who can tolerate IV melphalan.

Session Amyloid and Inflammatory Myocardiopathy

Study: Long-Term Survival in Patients with Primary Systemic Amyloidosis With Biopsy Proven Cardiac Involvement Presenter: Martha Grogan, Mayo Medical SChool, Rochester, Minn.

Results: Cardiac involvement is common in primary systemic amyloidosis with congestive heart &ilure, accounting for 5096 of all deaths.The median survival once there is cardiac involvement is 5 months.The purpose of this

June 1998

study was to evaluate the frequency of long-term survival in patients with primary systemic amyloidosis with biopsy-proven cardiac involvement. This study was a chart review from 1965 to 1997, with most patients seen after 1975. One hundred fifty-three patients were identified, and only eight (5%) survived for at least 45 months; seven of the eight survived longer than 10 years.All eight received chemotherapy. Median survival of the remaining 144 patients was 6 months. Patients with long-term survival had a trend toward higher ejection fractions (55% ± 12% vs 47% ± 14%)and longer mean mitral deceleration times (196 ± 71 vs 166 ± 45 msec).There was no significant difference in septal wall thickness (15 ± 4 mm vs 16 ± 3 mm,p =not significant).

Interpretation: Although the majority of patients with primary systemic amyloidosis have a poor prognosis, long-term survival is possible after treatment with chemotherapy. Chemotherapy can cause some regression of cardiac changes in long-term survivors. However, other patients with long-term survival had no changes in serial echocardiograms. Long-term survivors tended to have higher initial ejection fraction and longer mitral deceleration times.