Complement Inhibitor Has Little Effect in Either COMMA or COMPLY
Two reports on studies using the complement-inhibitor pexelizumab in this week’s issue of the journal Circulation cast doubt on the drug’s future. It appeared to have no effect on the size of infarct and equivocal effect on mortality in the patients suffering acute myocardial infarction. Complement is implicated in the inflammatory pathways associated with damage in myocardial infarction, and as an inhibitor, pexelizumab was expected to short-circuit the harm caused by the process.
In the COMMA trial (COMplement inhibition in Myocardial infarction treated with Angioplasty; Circulation. 2003;108:1184–1190), 960 patients with ST-segment–elevated myocardial infarction who were scheduled to undergo angioplasty were randomized to placebo, 2-mg/kg bolus of pexelizumab, or 2-mg/kg bolus of pexelizumab with 0.05-mg/kg infusion hourly for 20 hours. The treatment had no effect on infarct size, wrote the investigators, with Christopher Granger, MD, of Duke Clinical Research Institute in Durham, NC, as the lead author. Nor did the treatment have a significant effect on 90-day death, new or worsening heart failure, shock, or stroke. The 90-day mortality rate was lower in the pexelizumab group that received bolus in infusion—1.8% versus 5.9% in the placebo group. The bolus-alone group’s mortality rate was 4.2%. The bolus-plus-infusion group’s mortality rate was significantly lower than that of the placebo group.
The authors noted that although the treatment appeared to have no effect on infarct size, the lower death rate in the pexelizumab bolus–plus-infusion group indicates that the treatment may benefit patients by an alternative mechanism that deserves further study.
The authors wrote: “For the first time, an adjunctive therapy to protect the myocardium during reperfusion has resulted in reduced mortality. These results suggest the need for additional investigation of pexelizumab as an adjunctive treatment for acute ST-segment–elevation MI [myocardial infarction], particularly in the setting of mechanical reperfusion.”
COMPLY (COMPlement inhibition in myocardial infarction treated with thromboLYtics; Circulation. 2003;108:1176–1183) found that although pexelizumab blocked the activity of complement in patients who had suffered an acute myocardial infarction, neither the size of the infarct nor the number of adverse clinical outcomes was reduced.
In this study, which combined the complement-inhibitor with thrombolytics, 943 patients with acute ST-segment myocardial infarction who received clot-buster or fibrinolysis therapy were assigned to receive placebo, pexelizumab in a 2-mg/kg bolus, or pexelizumab in a 2-mg/kg bolus with 0.05-mg/kg hourly infusion for 20 hours. All patients were assigned to their treatment groups less than 6 hours after the onset of symptoms. The study’s researchers, led by Kenneth Mahaffey, MD, also of Duke Clinical Research Institute, wrote: “In conclusion, pexelizumab had no measurable effect on infarct size assessed by CK-MB release or on clinical outcomes when used as an adjunct to fibrinolysis.”
European Society of Cardiology Congress 2003
VIENNA, Austria—The European Society of Cardiology Congress, the largest medical society meeting in Europe, crowded this gracious middle European city with thousands of cardiologists, nurses, and other medical personnel from August 31, 2003, through September 3, 2003. New versions of old drugs took center stage in most reports, drawing overflow crowds to the rooms where researchers revealed the newest information from completed trials in hotline sessions.
Bullish on EUROPA
VIENNA, Austria—Angiotensin-converting enzyme (ACE) inhibitors appear headed toward acceptance as additional treatment for most, if not all, patients with coronary heart disease, concluded researchers and experts after presentation of EUROPA (The EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary artery disease).
The ACE inhibitor called perindopril prevented one cardiovascular death, nonfatal myocardial infarction, or cardiac arrest for every 50 patients with coronary artery disease who took 8 mg of the drug daily for 4 years, according to Kim M. Fox, MD, Professor of Cardiology at the Royal Brompton Hospital in London. He estimated that the effect would translate into the prevention of roughly 250 000 such events in the United States every 4 years.
“We would like to recommend to you, to the governments, to the people who write guidelines for the instruction of how doctors should manage patients that perindopril should be considered as chronic therapy for all patients with coronary artery disease,” said Dr Fox, who chaired the study. It was the largest ever carried out studying the use of ACE inhibitors in patients with heart failure.
“The purpose of this trial was secondary prevention. As doctors, the most important thing we can do is to prevent the disease that is killing us and our patients across the Western world. That is coronary disease,” said Dr Fox.
“This expands the spectrum of drugs that should be used in patients with chronic coronary artery disease,” said Michal Tendera, MD, Professor of Medicine at the Silesian School of Medicine, Katowice, Poland, and President-elect of the European Society of Cardiology. “Even on top of platelet inhibitors, statins, and β-blockers, there is a lot of space for ACE inhibitors. That is the significance of this study.”
“I think the findings for perindopril and ACE inhibition in EUROPA are so strong one would have to question why this would not be part of primary treatment,” said Sidney Smith, MD, Professor of Medicine and Director of the Center for Cardiovascular Science at the University of North Carolina at Chapel Hill, who commented during the session.
The trial involved 12 218 patients with known heart failure who were already receiving standard of care, such as aspirin, β-blockers, and lipid-lowering therapy. The patients were randomized to receive either 8 mg of perindopril daily or placebo.
“This study captures all patients with coronary disease,” said Dr Fox. “Many patients were asymptomatic, but all had proven coronary disease.”
The fact that the study found a 20% relative risk reduction over the 4.2 years of follow-up in the perindopril group was important because it occurred across all subgroups, said Dr Fox. “It worked in all circumstances with known risk factors for coronary disease.”
The 11% reduction in total mortality was not statistically significant, he said. However, the risk reduction for fatal and nonfatal myocardial infarction was 24%.
“The importance of this finding is reflected in the number of people with coronary disease. In Europe, we know of 20 million, and there are almost as many again of whom we don’t know who don’t present in the doctor’s office until they die or have a myocardial infarction,” said Willem J. Remme, MD, PhD, Director of the Sticares-InterACT Research Institute, Rotterdam-Rhoon, the Netherlands, and a co-chairman of the study. The Lancet published a report of the trial online September 1, 2003, at its website http://www.thelancet.com/ journal/vol362/iss9385/full/llan.362.9385.early_online_ publication.27047.1.
Dr Smith said EUROPA provides information that will be critical to development of secondary prevention strategies and guidelines. He said that indications from this study and those that have gone before mean to him that the effect is caused by the class of drugs called ACE inhibitors.
“We have known for 10 years that ACE inhibitors benefit patients after myocardial infarctions when they have impaired ventricular function. The question was whether they would help all patients.”
Current guidelines say physicians should “consider” the use of ACE inhibitors in all patients with coronary artery disease, he said. “We used the word ‘consider’ because we felt we needed more evidence,” he said. “Now we may be forced to reconsider the use of the word ‘consider.’”
The CHARM of Candesartan
VIENNA, Austria—The CHARM (Candesartan in Heart failure—Assessment of Reduction in Mortality and morbidity) of angiotensin II receptor blockers (ARBs) appears most evident in heart failure patients who are intolerant of ACE inhibitors, said researchers and experts at the Congress.
CHARM was a complicated study that evaluated the effect of candesartan, an angiotensin II receptor blocker, in three different groups of heart failure patients. The data from the study were amalgamated and reported as CHARM Overall.
The data also were reported separately, with data analyzed for each of the three groups. CHARM Alternative enrolled 2028 patients with heart failure and ejection fractions of less than 40% who were intolerant of ACE inhibitors. All were on other appropriate heart failure medications.
CHARM Added enrolled 2548 patients with heart failure and ejection fractions less than 40% who were taking an ACE inhibitor in addition to other appropriate medications. The third group, called CHARM Preserved, consisted of 3025 patients with heart failure who had ejection fractions equal to or greater than 40%. All were randomized to receive either candesartan or placebo. Candesartan was started at between 4 and 8 mg daily and titrated toward a target dosage of 32 mg. The average dose of candesartan after 6 months was 24 mg daily.
“There was a 16% relative risk reduction in heart failure–related hospitalizations or cardiovascular death in the candesartan-treated group,” said Marc A. Pfeffer, MD, Professor of Medicine at Harvard Medical School, who presented the results from the overall study. The risk reduction for cardiovascular death across all the groups was 12%. The risk reduction for heart failure–related hospitalization was 21%, he said.
In addition, he said, 163 of 2715 patients on candesartan and 202 of 2721 in the placebo group developed diabetes, a difference that is statistically significant. A total of 5346 patients did not have diabetes when enrolled in the trial.
A 15% relative risk reduction for heart failure–related hospitalization and cardiovascular death was reported in the candesartan patients in the CHARM Added portion of the trial, which included 2658 heart failure patients with ejection fractions equal to or less than 40%.
John McMurray, MD, Principal Investigator for the Glasgow University arm of the study, said the rationale of this arm of the trial was to determine if the addition of the ARB could improve patient risk profiles even when they are also taking an ACE inhibitor. CHARM Added patients were monitored the longest—an average of 41 months—and were also the sickest, with 73% of them in New York Heart Association class III.
“There was a 4.4% absolute risk reduction and 15% relative risk reduction,” he said. “This trial suggests that the addition of candesartan leads to a reduction in relevant cardiovascular events.”
Although most trials focus on heart failure patients with low ejection fractions, CHARM Preserved evaluated the use of candesartan in patients with ejection fractions of 40% or more, said Salim Yusuf, MD, DPhil, Professor and Director of the Division of Cardiology at McMaster University, Hamilton General Hospital in Hamilton, Ontario, who directed that arm of the study.
With 3023 patients, CHARM Preserved was the biggest arm of the trial. Although the use of candesartan was associated with a trend toward reduction in cardiovascular deaths or heart failure–related hospitalizations, the numbers did not reach statistical significance, said Dr Yusuf. There was no difference in cardiac deaths between the groups, but 402 patients were hospitalized for heart failure reasons in the candesartan group, compared with 566 in the placebo group.
“We cannot exclude the possibility of benefit,” said Dr Yusuf during his hotline presentation. “While I acknowledge that there is only the suggestion of benefit, physicians may consider using candesartan irrespective of ejection fraction.”
Results from CHARM Alternative provided the clearest information affecting clinical practice. Christopher Granger, MD, a Professor of Medicine at Duke University Medical Center in Durham, NC, noted that there was a 23% relative risk reduction of cardiovascular death or heart failure–related hospitalization in the portion of the 2028 patients with ejection fractions less than or equal to 40% who were randomized to either candesartan or placebo. All the patients were unable to take ACE inhibitors, he said.
Dr Granger estimated that as many as 10% of heart failure patients do not take ACE inhibitors because of intolerable side effects. He said there was a 15% relative risk reduction in cardiovascular death and a 32% relative risk reduction in heart failure–related hospitalization.
Indications of higher rates of renal problems and other problems related to candesartan that are usually seen in drugs of its class led the researcher to urge that patients be closely monitored to avoid dangerous side effects.
“I think it’s decided that candesartan can be used in those who cannot tolerate ACE inhibitors,” said Philip A Poole-Wilson, MD, PhD, Professor of Cardiology at the Imperial College School of Medicine in London and the invited commenter on the study at the Congress.
However, he said, in the CHARM Preserved portion that treated patients with higher ejection fractions, there was no evidence of efficacy in terms of cardiovascular deaths or heart failure–related hospitalization. “These data are to me less than convincing that these patients should be treated in this way,” he said.
If an ARB is prescribed for patients in the class represented by CHARM Added, he said, it would be the eighth drug those patients are taking, a prospect that many would find daunting.
He said it was “controversial” that the researchers had chosen to look at cause-specific mortality and hospitalization because it made comparisons among studies difficult. Yet he said that CHARM “is an enormous contribution to clinical medicine. You cardiologists will have to make up your minds as to how to use it in clinical practice.”
“CHARM shows the benefit of candesartan at least for patients who cannot tolerate ACE inhibitors, and as many as 20% of them cannot,” said Sidney Smith, MD, Professor of Medicine and Director of the Center for Cardiovascular Science at the University of North Carolina at Chapel Hill. “The addition of an ARB may be helpful for those on ACE inhibition, and for those with left ventricular ejection fractions greater than 40%, the value of the ARB needs stronger study.”
He said he believes that there is an indication that the effect seen with candesartan in this study may be a “class” effect—one that can be seen with other angiotensin II receptor blockers. He said that he was interested in the report on reduction in new-onset diabetes, similar to that seen in the HOPE (Heart Outcomes Prevention Evaluation) study that was reported on at an earlier meeting.
Four reports outlining the various portions of the CHARM study appeared online at The Lancet website on September 1, 2003. They can be found at http://www.thelancet.com/ journal/vol362/iss9385/full/llan.362.9385.early_online_ publication. 27043.1, http://www.thelancet.com/journal/vol362/iss9385/full/llan.362.9385.early_online_publication.27044.1, http://www.thelancet.com/journal/vol362/iss9385/full/llan.362.9385.early_online_publication.27045.1, and http://www.thelancet.com/journal/vol362/iss9385/full/llan. 362.9385.early_online_publication.27046.1.
ON-TIME and GRACIA-2 Seek Faster, Better Care for Acute Myocardial Infarction
VIENNA, Austria—Two studies at the second hotline session at the European Society of Cardiology Congress here August 30, 2003, through September 3, 2003, seek to improve treatment of patients with myocardial infarction who will eventually end up undergoing a percutaneous coronary intervention or a coronary artery bypass graft surgery.
In the ON-TIME (Ongoing evaluation of Tirofiban In Myocardial infarction Evaluation) trial, researchers from the Netherlands evaluated the value of giving tirofiban before ambulance transport in patients who had had a myocardial infarction. Arnoud W.J. van’t Hof, MD, PhD, of the Isala Klinieken in Groot Wezenland in the Netherlands, told the session, “Tirofiban is attractive for early facilitation of primary angioplasty on top of aspirin.”
Flavio Ribichini, MD, of Laboratorio di Emodinamica, Ospedale Santa Croce in Cuneo, Italy, agreed that “tirofiban given early in the emergency room or during transport offers moderate improvement in epicardial flow compared to tirofiban given late in the cath lab during PCI [percutaneous intervention] in patients with AMI [acute myocardial infarction].”
He was less impressed with the drug’s prowess than with the ability of the Netherlands’ health personnel to deliver care quickly and efficiently during the trial. “When a concomitant pharmacologic treatment is planned for emergency PCI in acute myocardial infarction, the earlier the treatment with tirofiban is started, the better the angiographic presentation. The most impressive result is not associated with the study drug but the demonstration that pretreatment delay can be largely reduced with expected clinical benefits.”
In the study, 507 patients were randomly assigned to receive treatment by two different paths. Those in the early tirofiban path received treatment in the ambulance or emergency room as soon as it was determined that they were having or had had an acute myocardial infarction. They were then transferred by ambulance to a center where percutaneous intervention could be carried out. They underwent angiography, received a placebo, and then underwent percutaneous intervention, if it was deemed appropriate.
Those in the late tirofiban group received a placebo before transport and then went by ambulance to an appropriate center, where they had an angiogram. They received tirofiban then and underwent percutaneous intervention if appropriate. All patients received unfractionated heparin and aspirin, along with other treatments if necessary, the researchers said.
The primary end point was TIMI (thrombolysis in myocardial infarction) 3 flow at first angiography after the procedure, indicating that the affected artery is open. Dr van’t Hof said 19% of patients in the early treatment group achieved TIMI 3 flow at first evaluation, compared with 15% in the late tirofiban group. The difference, he said, was not statistically significant.
Dr Ribichini pointed out that the patients in the study were managed in much the same way that trauma patients received care, with transport to the best center rather than the nearest. On average, patients received their angioplasties 94 minutes from the time they were first evaluated, either in the ambulance or in the emergency room.
“The 40-minute in-hospital delay is remarkable,” he said. “This study supports the importance of early treatment in acute myocardial infarction and high-quality emergency care.”
In GRACIA 2 (Grupo de Análisis de la Cardiopatiá Isquémica Aguda), Francisco F. Avilés, MD, and his colleagues were seeking a method of offering high-quality therapy to patients for whom primary angioplasty is not readily available. As many as 80% of patients in the Western world do not have access to primary angioplasty within the necessary time, he said.
His study showed that combining a thrombolytic called tenecteplase with later percutaneous intervention had a result nearly equal to that of primary percutaneous intervention.
In one arm of the study, 108 patients with acute myocardial infarction were randomly assigned to undergo primary percutaneous intervention. In the other, they used what they called “facilitated intervention.” The 104 randomized patients immediately received thrombolysis with tenecteplase and then received enoxaparin. When they arrived at the center capable of performing percutaneous intervention, they were assigned to adequate revascularization within 3 to 12 hours. Three deaths occurred in the facilitated group and 6 in the primary percutaneous intervention group.
There was no difference in terms of death, reinfarction, need for urgent surgery, or new intervention between the two groups, said Dr Avilés. “The percentage of bleeding complications was similar as well.”
He said, “This suggests that both strategies are similarly effective in restoring myocardial perfusion, preserving left ventricular function, and benefiting clinical outcome.”
“This intervention is an approach to treatment that is available worldwide,” said Dr Avilés. “It seems to be safe and the effects are as optimal as primary stent-angioplasty. The proportion of heart attack patients who could benefit from angioplasty would increase dramatically” with this kind of intervention.
Franz Van der Werf, MD, PhD, Professor and Chairman of the Department of Cardiology at the University Hospital Gasthuisberg, Leuven, Belgium, said the “pilot study lends support to a combined pharmacological mechanical strategy. These encouraging results of GRACIA-2 need to be confirmed in much larger studies.” He said such studies are now underway, and the information should be available by 2005.
Opening the Channels: When, How, and With What?
Opening the affected arteries of low-risk patients who have had an acute myocardial infarction 12 hours before may provide them with no benefit while exposing them to risk, said Phillipe Gabriel Steg, MD, of the Hôpital Bichat in Paris.
Dr Steg and French colleagues carried out the DECOPI (DEsobstruciton COronaire en Post-Infarctus) study. In that trial, patients who sought treatment 12 or more hours after the onset of their heart attacks were randomized to receive either best medical treatment or percutaneous intervention. All patients received aspirin, β-blockers, and an ACE inhibitor if ventricular function was less than 40%.
A total of 212 patients were randomized—103 to medical treatment and 109 to angioplasty, Dr Steg said. He and his colleagues had planned to enroll more, but enrollment was difficult, and eventually the Data Safety Monitoring Board stopped it, he said.
The physicians performed percutaneous intervention a median of 8 days after the event in patients randomized to that group, he said. After follow-up of 33 to 35 months, there was no difference in the primary end point, with 8.7% in the medical arm and 7.3% in the percutaneous intervention arm experiencing cardiac death, nonfatal myocardial infarction, or ventricular arrhythmias.
Patency of the affected artery was 39.7% in the medical arm and 82.7% in the percutaneous arm, he said. Although the difference was not statistically significant, it was narrower than expected, he said. The major difference was cost. Treatment for those in the medical arm was 12 469 Euros, whereas the percutaneous arm was more than 1000 Euros more at 13 484.
The study proves that systematic late percutaneous intervention was of limited value in a low-risk group, he said. “It might be more beneficial in a higher-risk group,” said Dr Steg.
“Does DECOPI kill the open-artery hypothesis?” asked Eugene Braunwald, MD, Professor of Medicine at Harvard University Medical School in Boston. “I don’t think so, although I can’t deny some bias.”
He pointed out that DECOPI enrolled a low-risk population with two thirds of the patients having single-vessel disease. The left anterior descending artery was the target vessel in only 17% of patients. Patients in both groups were treated for the most part with aspirin, β-blocker, ACE inhibitors, and statins. Dr Braunwald said this contributed to the extremely low event rate.
“A trial of many thousands of patients would be required to show benefit in such a low-risk group,” he said. “Therefore, at 212 patients, DECOPI was greatly underpowered. Fortunately, the Open Artery Trial (OAT), which is now ongoing, meets some of these requirements. This trial is led by Dr Judith Hochman of New York and has now enrolled more than 1400 of a planned 3200 patients 3 to 28 days post AMI. These patients are regarded to be at high risk because of an impaired EF [ejection fraction] or proximal occlusion of a large coronary artery.”
In a trial involving a drug-eluting stent, E-SIRIUS (European multicenter randomized, double-blind study of the SIRolImUS-coated balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions), only 5.9% of patients who received the coated stent experienced restenosis, compared with 42.3% of those who received the bare stent, said Joachim Schofer, MD, of the Hamburg (Germany) Heart Center. He said this translated into an 86% relative risk reduction for the coated stent group.
At 9 months, the incidence of major adverse cardiac events (death, myocardial infarction, and target lesion/vessel revascularization) was significantly reduced, with 8% in the coated stent group and 22.6% in the control group.
A total of 352 patients enrolled in the study, with 177 in the bare stent group and 175 in the coated stent group. In addition, said Dr Schofer, 45 patients who received the sirolimus-eluting stent underwent direct stenting, as did 47 of those in the control group. There was no statistically significant difference between the patients who underwent direct stenting and those who received balloon angioplasty followed by the stent.
“Direct stenting is cheaper,” said Dr Schofer, and “it appears as efficacious and safe as predilatation and stenting.”
Sigmund Silber, MD, Professor of Medicine at the University of Munich, complimented the study, but he pointed out that there was no randomization for the direct stenting, which means that the results are less significant. The fact that the primary end point of the study was angiographic also was disappointing, he said.
“The goal is not to improve angiographic parameters like restenosis rate, in-stent median lumen diameter, or late lumen loss,” he said.
A new oral anticoagulant called ximelagatran reduced the risk of death, recurrent heart attack, or angina by 6.4% in patients with recent heart attack, said Lars Wallentin, MD, Professor of Cardiology at the Uppsala Clinical Research Center in Uppsala, Sweden. The ESTEEM (Efficacy and Safety of The oral direct thrombin inhibitor ximelagatran in patients with recent myocardial damage) trial was the first trial of this drug in these patients.
The double-blind, placebo-controlled study involved 1883 patients at 191 hospitals in 18 countries between 2001 and 2002. Patients, all of whom were on aspirin, were randomized to 6 months of treatment with either placebo or one of 4 doses of the drug—24 mg, 36, mg, 48 mg, or 60 mg given twice daily. The results were similar for all groups, and Dr Wallentin said he thought that the 24-mg dose would be taken on to larger trials.
The use of the drug was associated with a risk of liver enzyme elevation, he said. However, he said the elevation was usually transient and decreased toward normal over 1 to 3 months.
Ximelagatran complements the antiplatelet effect of aspirin, said Dr Wallentin. “It is better than aspirin alone in reducing death, myocardial infarction, and severe recurrent ischemia.”
“ESTEEM supports the concept that an oral direct thrombin inhibitor reduces arterial thrombotic events,” he said. “However, we need confirmatory phase II trials.”
Freek W.A. Verheught, MD at the Heart Center at Nijmegen, the Netherlands, asked 3 major questions: “Why was there no dose response?” he asked. He advised picking out the most effective dosage level with lowest risk of bleeding.
“The liver enzyme abnormalities are a problem,” he said. “If we trade ximelagatran for coumadin, do we have to replace the INR [international normalized ratio] monitoring with liver function monitoring?”
He said he would also like to see a comparison of ximelagatran with clopidogrel against clopidogrel alone in this population.
He sees possibilities for using this anticoagulant early in acute coronary syndrome with or without perfusion therapy, in the catheter lab, and with artificial heart valves. ESTEEM was published online in The Lancet at http://www.thelancet.com/ journal/vol362/iss9385/full/llan.362.9385.early_online_publication. 27048.1.