Special Report From The 2007 American College of Cardiology Annual Meeting, New Orleans
COURAGE
SPECIAL REPORT FROM THE 2007 AMERICAN COLLEGE OF CARDIOLOGY ANNUAL MEETING, NEW ORLEANS
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Source: Boden, WE, et al. Optimal Medical Therapy With or Without PCI for Stable Coronary Disease. N Engl J Med. 2007; Online.
This long awaited study tested the hypothesis that aggressive pharmacologic therapy and lifestyle intervention (Optimal Medical Therapy or OMT) without percutaneous coronary intervention (PCI) would not be as successful in reducing major cardiovascular events as OMT in addition to PCI. COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) was a randomized trial conducted at fifty centers in the United States and Canada, with randomization between 1999 and 2004, assessing a primary outcome of nonfatal myocardial infarction (NFMI) or death from any cause during follow up of 2.5 to 7.0 years (median, 4.6 years). The COURAGE trial sought to test whether or not PCI reduced major cardiac events, and particularly NFMI and death, as previous studies have not conclusively demonstrated that PCI does more than decrease angina frequency and enhance exercise performance. The study enrolled 2,782 stable CAD subjects with significant angina and a stenotic lesion > 70% in an epicardial coronary artery with evidence of ischemia on stress testing. The latter ranged from routine treadmill -test evaluation to nuclear techniques; exclusionary criteria included > 80% coronary artery narrowing with classic angina, severe angina, a strongly positive stress test, heart failure, ejection fraction of < 30%, revascularization within 6 months, or coronary anatomy not suitable for PCI.
Patients were assigned to PCI and OMT, or OMT alone. Medical therapy consisted of aspirin or clopidogrel; metoprolol; amlodipine; isosorbide mononitrate, as well as an ACE inhibitor or ARB. Targeted lipid lowering therapy strove to achieve a LDL level of less than 85 mg/dl with simvastatin with or without ezetimibe. In the PCI group, target lesion revascularization was carried out and complete revascularization was encouraged. PCI success was < 50% stenosis after balloon angioplasty, and < 20% narrowing after stent implant. Clinical success was defined as angio--graphic success with no major complications. There was virtually no use of drug-eluting stents, which were not yet available for most of the study period. Many secondary outcomes were assessed, including stroke and hospitalization for unstable angina. The investigators projected major event rates of 21% in the medical therapy group and 16.4% in the PCI patients over a follow up of 2.5-7 years.
RESULTS: Multiple baseline characteristics were similar in the 2 groups. Median angina frequency was 3 attacks per week; 58% of subjects had Canadian Class II-III angina. Ninety percent of patients undergoing myocardial perfusion imaging had reversible defect(s) consistent with inducible ischemia; two thirds of the patients had multi-vessel CAD; 94% of PCI patients received at least one stent (40% more than one stent). Vessel stenosis was reduced from 83 +/- 14% to 31 +/- 34% in non-stented patients. PCI success was 93%; clinical success (all lesions dilated and no complication) occurred in 89% of randomized patients. Medication compliance was excellent; at 5 years 70% of individuals had an LDL < 85 mg/dl; blood pressures were within normal range, and half of all diabetics had a hemoglobin A1C of 7.0% or less. Smoking decreased and exercise increased during the course of this study, with a median follow up of 4.6 years. The primary outcome of death or NFMI occurred in 211 PCI patients and 202 medical therapy patients, with an estimated 4.6 year cumulative primary event rate of 19% in both groups. Secondary outcomes including stroke, were slightly higher at approximately 20% in each group. Other endpoints included hospitalization for ACS, rate of MI and death, all with identical event curves. The primary endpoint was met in 16.2% and 17.9% in the PCI and medical groups, respectively, p = 0.29. At follow up, 21% of PCI subjects and 32% of medical therapy patients had undergone revascularization, hazard ratio 0.60, p < 0.001. Revascularization occurred for intractable angina or worsening ischemia on noninvasive testing. Angina prevalence declined in both groups with a statistically significant difference throughout most of the study in favor of PCI. However, at 5 years 74% of PCI patients and 72% percent of medical therapy patients were free of angina. There were no interactions between any subgroups.
The authors conclude that, "As an initial management strategy, PCI added to optimal medical therapy did not reduce the primary composite endpoint of death and NFMI as compared with optimal medical therapy alone." The COURAGE cohort was high risk, as patients had to have objective evidence of ischemia and most had extensive CAD on angiography. The authors nicely discuss the pathophysiology of stable CAD vs vulnerable plaques (responsible for ACS). They conclude that "focal management…of severely stenotic lesions with PCI…did not reduce the rate of death and MI." The medical therapy group had event rates lower than anticipated, presumably related to intensive medical therapy that included exercise and smoking cessation. Both PCI and OMT patients had a significant improvement in angina, favoring PCI/ OMT individuals in the early years, with equivalent angina rates at the end of the study. The authors stress that prior studies, including their data, have consistently demonstrated that "PCI has no effect in reducing major cardiovascular events." Thus, the data are consistent with clinical practice guidelines, allowing deferral of PCI in patients with stable coronary disease, even if multi-vessel and associated with inducible ischemia, so long as "intensive multifaceted medical therapy is instituted and maintained." One-third of the OMT group subsequently required revascularization during the study and angina rates were clearly improved in the PCI patients more than the OMT subjects. Of importance, PCI added to ideal medical therapy decreased angina but not death, NFMI, or hospitalization for ACS.
Commentary
This very important report will generate considerable discussion and analysis over the ensuing months and years. The study was well designed and conducted. It will be tempting, but inappropriate for some to extend the results of COURAGE to other subsets, such as patients with accelerating or unstable angina or subjects with no chest pain at all, with or with out positive stress testing for ischemia. A critical analysis of COURAGE clearly documents the high-risk state of both treatment groups, with a major event rate of approximately 4% per year. It is important to note that hospitalization for ACS in the total nonfatal MI population was equivalent in both cohorts. COURAGE patients were at least moderate risk, indicated by the inclusion criteria of at least one stenotic major coronary artery, inducible ischemia and active angina attacks, although clinically stable. This study does not address acute coronary syndromes, where the benefit of PCI with anti-platelet therapy has been demonstrated repeatedly. Neither does the data address the issue of early vs late catheterization after ACS, as this was a stable angina population. However, the medical therapy utilized in COURAGE is the same as outlined in ACC/AHA guidelines for treatment of angina, and reflects the increasingly aggressive cardio-protective therapy that is being delivered in many centers today. One would hope that these results may decrease unnecessary PCI, such as in patients with no chest pain, even with a positive stress test. The investigators are to be congratulated on a landmark clinical study that should cause all individuals treating patients with CAD reflect on the actual study details and incorporate the COURAGE lessons into clinical practice.
FUSION II
SPECIAL REPORT FROM THE 2007 AMERICAN COLLEGE OF CARDIOLOGY ANNUAL MEETING, NEW ORLEANS
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
The follow-up serial infusions of nesiritide for the Management of Patients with Heart Failure (FUSION II) Trial was presented by Dr. Clyde Yancy, Director of the Baylor Heart and Vascular Institute in Houston. This trial of chronic decompensated heart failure patients evaluated the role of recombinant human B-type natriuretic peptide given as a 4-6 hour infusion once per week or twice per week vs a placebo infusion. The primary end point was the time to death from cardiovascular events or renal events requiring hospitalization over the 12 weeks that the infusions were given. In the 920 patients studied, all had ejection fractions < 40% and two-thirds had ischemic cardiomyopathy. Baseline heart failure drug therapy was excellent and was continued; 25-30% had an electrophysiologic device in place. The trial was a follow-up to the FUSION I study, which showed that the nesiritide was safe and efficacious in advanced heart failure patients.
RESULTS: Event rates were 33% lower in FUSION II as compared to FUSION I, which this was probably due to improved use of optimal evidence-based management strategies. The results of FUSION II were neutral. The primary end point was achieved in 30% of both groups and mortality was 10% in both groups. The patients were followed for 24 weeks and there were no significant differences in outcomes. There were also no significant subgroup differences although there was a trend for African American patients to do better on nesiritide. The secondary end points, including quality of life, were also not different. With regard to safety, 88% had some adverse event and this was equal between the groups. Hypotension was the most common adverse event with nesiritide. Serious adverse events and renal adverse events were equal between the groups. The investigators concluded that in advanced heart failure patients, serial outpatient infusions of nesiritide did no harm, but were also not beneficial. They believed that optimal medical and electrophysiologic device therapy diminished the benefit of outpatient serial nesiritide infusions and explains the difference between the positive results in FUSION I and the neutral results in FUSION II. In the ensuing panel discussion, the conclusion was that serial outpatient nesiritide infusions should be abandoned. Dr. Yancy commented that the main message of FUSION II "is that adherence to guideline-driven therapy and meticulous follow-up defines the benchmark for care of patients with chronic decompensated stage D heart failure."
VALIDD
SPECIAL REPORT FROM THE 2007 AMERICAN COLLEGE OF CARDIOLOGY ANNUAL MEETING, NEW ORLEANS
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
The influence of angiotensin receptor blockers and blood pressure lowering on diastolic function in patients with hypertension and diastolic dysfunction: The Valsartan in Diastolic Dysfunction (VALIDD) trial was presented by Dr. Scott Solomon from the Brigham and Women's Hospital in Boston. The pathophysiologic theory behind this trial is that hypertension leads to left ventricular hypertrophy, which leads to increased left ventricular fibrosis and eventually leads to heart failure secondary to diastolic dysfunction. Consequently, the hypothesis is that if you treat the hypertension, then you can regress the left ventricular hypertrophy and possibly improve diastolic dysfunction. Since blockade of the renin angiotensin aldosterone system has been shown to decrease left ventricular hypertrophy and fibrosis, can these drugs improve diastolic dysfunction? Thus this randomized double-blind placebo-controlled trial was conducted on 384 patients over the age of 45 with stage 1 or 2 hypertension and echo Doppler evidence of diastolic dysfunction, who were treated with valsartan titrated up to 320 mg a day vs standard therapy. The target was a blood pressure less than 135/80 using a combination of diuretics, beta-blockers, calcium-blockers, and alpha-blockers in the control group. Diastolic function was estimated by tissue-Doppler imaging on echocardiography of the lateral annulus in the 4-chamber view. The primary end point of the study was changes in E' velocity. Other diastolic parameters were secondary end points. Of the 384 patients enrolled in the trial, all had normal BNP levels and no symptoms of heart failure. At baseline, echo variables were not different between the 2 groups; 12% were African American and more than one-half had abnormal cholesterol levels. Blood pressure was significantly reduced by therapy in both groups and the degree of reduction was not different at the end of 38 weeks of therapy. The primary end point of E' increased in both groups to 8.1 in the valsartan group versus 8.0 in the placebo group, which was not significantly different. The change in E' correlated with blood pressure reductions, but the effect was nonlinear. Isovolumic relaxation time and S' were better on valsartan, but E/E' E/A were/was not. LV mass also decreased in both groups, but there was no significant difference between groups. The investigators concluded that in patients with mild to moderate hypertension and diastolic dysfunction that lowering blood pressure either with valsartan or other drugs improves diastolic dysfunction and reduces LV mass. In the discussion that ensued, it was pointed out that renin angiotensin aldosterone-blocking drugs have never been shown in clinical trials to do more than lower blood pressure, which is known to be beneficial. Whether there are other benefits beyond blood pressure lowering are still unknown. Dr. Solomon commented that the results "suggest that one of the benefits of treating hypertension may be to improve diastolic function, even in patients with mild hypertension," which may reduce the risk of developing heart failure.
ILLUSTRATE
SPECIAL REPORT FROM THE 2007 AMERICAN COLLEGE OF CARDIOLOGY ANNUAL MEETING, NEW ORLEANS
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
The cholesterol ester transfer protein (CETP) inhibitor torcetrapib has been shown to raise HDL levels significantly. In the ILLUSTRATE trial 1,188 patients with any HDL-cholesterol ( C ) level and a clinical indication for cardiac catheterization were randomly assigned to receive atorvastatin plus torcetrapib or atorvastatin alone. The effects of the drugs on an intra vascular ultrasound analysis of coronary atheromas were assessed initially and after months of treatment on torcetrapib. There was an amazing 61% increase in HDL-C and a 20% decrease in LDL-C, which achieved an average LDL:HDL ratio of < 1. Also, torcetrapib increased systolic blood pressure by 5 mmHg. Despite the dramatic beneficial effect on lipids, torcetrapib did not reduce progression or induce regression of coronary atherosclerosis. The principal investigator who presented the trial Dr. Steven Nissen said that these disappointing results should not completely negate the CETP-inhibitor class of drugs, since newer agents may prove to be better.
RADIANCE I & II
SPECIAL REPORT FROM THE 2007 AMERICAN COLLEGE OF CARDIOLOGY ANNUAL MEETING, NEW ORLEANS
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
The results of the effect of torcetrapib and atorvastatin compared with atorvastatin alone on carotid intimal-media thickness in subjects with hyperlipidemia (RADIANCE) trials were presented by Dr. John Kastelein. The RADIANCE I trial involved patients who were heterozygote for familial hypercholesterolemia. They were randomized to either atorvastatin at an average dose of 56 mg a day vs atorvastatin plus torcetrapib. They were followed for one year by measuring carotid intimal-media thickness in 12 sites in the common carotid and the bifurcation. Over the course of a year, 14 patients dropped out of the trial. Dr. Kastelein, who is professor and chairman of the department of vascular medicine at the academic medical center in Amsterdam, said that the curves for the primary end point of change in carotid atheroma volume "were flat as a Dutch pancake." In other words, not only were the results in the 2 groups not significantly different, there was no trend and there was no improvement by either therapy in carotid intimal media thickness. Interestingly, overall systolic blood pressure was increased by 3 mmHg with torcetrapib. These results occurred despite marked increases in HDL, decreases in LDL, increased apolipoprotein A and decreases in B in the torcetrapib group. RADIANCE II involved patients with mixed dyslipidemia also followed for one year with a 24% discontinuation rate. The mean atorvastatin dose was 13 mg/day. In these patients HDL levels almost doubled and LDL levels were decreased by 18%. The primary end point of carotid intimal-medial thickness atheroma volume was not significantly different. Severe cardiovascular adverse events were somewhat more on torcetrapib at 10% vs 6% in the atorvastatin alone group. Also in the torcetrapib group a 5 mmHg average increase in blood pressure was noted. The investigators concluded that there was no regression of atherosclerosis despite very favorable lipid effects using torcetrapib.
ERASE
SPECIAL REPORT FROM THE 2007 AMERICAN COLLEGE OF CARDIOLOGY ANNUAL MEETING, NEW ORLEANS
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
The effect of reconstituted high-density Lipoprotein on Aatherosclerosis: Safety and Efficacy (ERASE) trial was presented by Jean-Claude Tardif, Director of Research at the Montreal Heart Institute. Infusions of r-HDL or placebo were randomly administered to 145 patients within 2 weeks of an acute coronary event. Either 40 mg or 80 mg per kg were administered over a 4-week period. Coronary angiography with intravascular ultrasound imaging was done before and after the infusions, and the primary end point was percent change in atheroma volume. Secondary end points included changes in plaque volume characteristics and the QCA score. The data safety and monitoring board recommended discontinuation of the 80 mg arm because of liver function test abnormalities. Ninety percent of the patients were also on statins. The primary end point decreased 3.4% on r-HDL vs 1.6% on placebo, which was not statistically different. The secondary endpoints of plaque characteristics improved significantly on r-HDL, but not on placebo. Also, QCA decreased on placebo, but not on r-HDL. Both of these were significant. Although mild hypotension was frequently observed with the r-HDL infusion, there was no significant difference in any safety end points in the 40-mg-per-kg group vs placebo. The authors concluded that atheroma volume was not significantly changed by r-HDL therapy even though there were favorable effects in CQA and plaque characteristics. Thus, since there were positive outcomes only for the secondary end points, this result was viewed by the discussants as a proof of concept study.
Direct Renin Inhibition
SPECIAL REPORT FROM THE 2007 AMERICAN COLLEGE OF CARDIOLOGY ANNUAL MEETING, NEW ORLEANS
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Dr. Suzanne Oparil presented the results of a study of the direct renin inhibitor aliskiren in combination with the angiotensin receptor-blocker valsartan compared with either agent alone in 1,797 patients with class 1-2 hypertension. This randomized placebo-controlled double-blind study titrated valsartan from 160 mg to 320 mg a day and aliskiren from 150 mg to 300 mg a day. The primary end point was change in diastolic blood pressure. Secondary end points were changes in systolic blood pressure, achieving the target blood pressure of < 140/90 and the 24-hour blood pressure profile. There was a significant decrease in blood pressure on valsartan and aliskiren monotherapy that was augmented by combination therapy. Changes in systolic blood pressure were similar and were seen over the entire 24-hour monitoring period. The overall average effect was an additional lowering by aliskiren of 4.5 mmHg systolic and 3.2 mmHg diastolic over valsartan alone at 4 weeks of therapy. Approximately two-thirds of the patients responded to combination therapy and showed results that were better than monotherapy. Plasma renin levels were increased on valsartan and decreased on aliskiren. The addition of aliskiren did not increase the number of adverse effects, but increased potassium was more common with the combination therapy. The investigators concluded that this was the first large-scale trial showing the blood-pressure lowering effects of dual renin system blockade with angiotensin receptor blocker and a direct renin inhibitor in patients with stage 1 to 2 hypertension. In the discussion that ensued, one commenter mentioned that the incremental benefit was small and was similar to what is seen with hydrochlorothiazide. Also, it was noted that there have been reports of angioedema, but it is rare, occurring in 4 out of 6,000 patients treated to date. Based on this study and others, it is clear that aliskiren is effective as monotherapy and adds to combination therapy regimens. Where its niche will be in treating patients with hypertension is not clear, but the low side effect profile may make it an attractive addition to combination therapy.
Studies taken from the American College of Cardiology Annual Meeting held in New Orleans.Subscribe Now for Access
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