Highlights from the American College of Cardiology Forty-Ninth Annual Scientific Sessions: March 18 to 21, 2001☆☆☆

Study: 

Angiographic patency of LIMA-LAD anastomosis after MIDCAB compared with conventional CABG: Results from the POEM trial

Presenter: 

Dr Roxana Mehran, Cardiovascular Research Foundation, Lenox Hill Heart and Vascular Institute, New York, NY

Background: 

Conventional coronary artery bypass grafting (CABG) (cardiopulmonary bypass + open sternotomy) with use of the internal mammary artery (IMA) has been performed for the last 20 years with excellent outcomes. The reported early patency varied from 91% to 98%, and the 1-year patency from 84% to 98%. Minimally invasive direct coronary bypass (MIDCAB) is a new technique in which IMA is anastomosed to the left anterior descending artery under direct visualization on a beating heart. Data on patency with this technique are promising but scarce. The Patency, Outcomes and Economics of MIDCAB (POEM) study was a multicenter, prospective trial to determine the relative merits of the newer MIDCAB compared with conventional CABG. The primary end point was combined clinical failure (death, myocardial infarction, major neurologic event, clinically driven target vessel revascularization) and angiographic anastomosis site failure (>75% diameter stenosis or <TIMI grade 3 flow) at 6 months.

Results: 

A total of 310 patients were enrolled in the POEM trial, 145 in the CABG arm and 165 in the MIDCAB arm. Baseline patient characteristics were similar in both groups. More vessels were bypassed with CABG than with MIDCAB (3.3 vs 1.0, P < .0001), and operating room time was significantly longer in the CABG arm (4.0 h vs 2.8 h, P < .0001). Patients undergoing MIDCAB had a significantly shorter time to extubation (12 h vs 3.2 h, P < .0002) and shorter length of stay (8.3 d vs 4.5 d, P < .001) than did those undergoing CABG. Patients in the MIDCAB group were less likely to have in-hospital complications (atrial fibrillation, bleeding, etc) than those in the CABG group. No differences were seen in death, myocardial infarction, or neurologic events between the 2 groups at 6 months. Patency at 6 months was similar in the patients undergoing CABG and MIDCAB (94.3% vs 93.1%, P not significant). No difference was observed in the occurrence of the combined primary end point between the 2 groups (98.5% vs 95.3%, P = .16).

Interpretation: 

This study has shown that similar results in terms of patency of LIMA-LAD anastomosis can be achieved with either conventional CABG or MIDCAB. All the other findings of this study should be interpreted with caution because it was not randomized but was a parallel registry of patients undergoing CABG or MIDCAB in the same institutions. Patients who underwent conventional CABG had more extensive coronary artery disease (multivessel revascularization) than did the MIDCAB patients (single-vessel revascularization).

Study: 

The West of Scotland Coronary Prevention Study (WOSCOPS): Three-year poststudy follow-up

Presenter: 

Professor S. M. Cobbe, Centre for Biostatistics and Department of Medical Cardiology, University of Glasgow, United Kingdom

Background: 

The WOSCOPS study demonstrated unequivocally the mortality and morbidity of treatment with pravastatin in primary prevention. It randomized 6595 men, 45 to 64 years old, with no history of myocardial infarction, to receive pravastatin (40 mg/dL) or placebo and followed them up for 4.8 years. At the end of the study, in addition to significant benefits on nonfatal events, there were 241 deaths and a 33% risk reduction in cardiovascular mortality (P = .033), a neutral effect on noncardiovascular mortality, and, overall, a 22% reduction in all-cause mortality (P = .051). The objectives of the current study were to examine whether the pravastatin-associated benefits seen during the trial were maintained after longer follow-up and also to determine whether lipid-lowering treatment is continued after study termination.

All 6345 subjects who completed the WOSCOPS study alive were invited to participate in the 3-year follow-up. A total of 5678 (89%) subjects agreed to participate. At the close of study, subjects were referred to their general practitioners for treatment of their raised cholesterol levels. All deaths were identified and adjudicated in a blinded fashion.

Results: 

Of the 387 patients who had a myocardial infarction or who had undergone revascularization during the initial study period, 32% had been started on a cholesterol-lowering drug at 12 months of study completion. Among patients who remained in primary prevention, only 12% of those originally assigned to placebo and 13.5% of those assigned to pravastatin had been initiated on a cholesterol-lowering treatment. More than 95% of those treated received a statin. There were 486 deaths, including in-trial events. The overall percent proportional risk reduction associated with treatment with pravastatin was 27% (hazard ratio [HR] 0.73 [95% confidence interval (CI) 0.56-0.96], P = .022), 6% for noncardiovascular deaths (HR 0.94 [95% CI 0.74-1.20], P = .64), and 16% for all-cause mortality (HR 0.84 [95% CI 0.7-1.0], P = .051).

Interpretation: 

The 3-year extended follow-up of the WOSCOPS recruits confirms the efficacy and safety associated with long-term treatment with pravastatin. However, initiation of treatment for elevated cholesterol levels was slow after the results of WOSCOPS were released.

Study: 

The relationship between on-treatment lipid levels and clinical outcomes: The Pravastatin Pooling Project

Presenter: 

Professor I. Ford, University of Glasgow, United Kingdom

Background: 

Although the subject remains controversial, epidemiologic data suggest that a decreasing gain in clinical benefit is achieved from aggressively reducing low-density lipoprotein cholesterol (LDL-C). The benefits to be gained by modifying high-density lipoprotein cholesterol (HDL-C) and triglycerides, in addition to LDL-C, are less clear. Therefore the prospective Pravastatin Pooling Project investigators evaluated the results of the West of Scotland Coronary Prevention Study (WOSCOPS),1 the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study,2 and the Cholesterol and Recurrent Events (CARE) study3 to examine the relationship between achieved levels of LDL-C and changes in LDL-C, HDL-C, and triglycerides.

The study was designed to investigate the variation in long-term benefits associated with modifying LDL-C, HDL-C, and triglycerides to different extents. At 12 months, patients in the pravastatin-treated groups were separated into quintiles of achieved levels of and changes in LDL-C, HDL-C, and triglycerides. Future coronary events rates were calculated and compared statistically after adjustment for baseline risk factors and lipids and other relevant on-treatment values.

Results: 

No significant evidence of heterogeneity of risk was found to be associated with variation in percentage change in HDL-C and loge (triglycerides). In CARE, achieved LDL-C was not associated with the risk of a coronary event (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.75-1.11, P = .377). In LIPID and WOSCOPS, where baseline LDL-C levels were higher, there was a positive association, primarily because of higher risk in subjects in the quintiles with the highest on-treatment LDL-C: >126 mg/dL in LIPID (HR 0.84, 95% CI 0.77-0.93, P = .000) and >164 mg/dL in WOSCOPS (HR 0.74, 95% CI 0.63-0.87, P = .000).

Interpretation: 

These findings are consistent with the concept of diminishing clinical benefit with greater LDL-C lowering. The study could not demonstrate additional benefit associated with greater changes in HDL-C and triglycerides levels. However, the changes in HDL-C and triglycerides were modest.

Study: 

Predictors of mortality in 560 patients with infective endocarditis: findings of the Multicentre Aspirin Trial in Infective Endocarditis (MATIE) study

Presenter: 

Dr Kwan-Leung Chan, University of Ottawa Heart Institute, Ottawa, Ontario, Canada

Background: 

The MATIE study was designed as a randomized controlled trial to assess the effect of aspirin on outcomes in infective endocarditis (IE). In addition, the investigators analyzed patients enrolled in the trial to assess the determinants of hospital mortality. A total of 560 patients was enrolled in the trial from July 1994 to June 1998 from 18 centers in Canada and 1 center in the United States. One hundred fifteen were randomized to aspirin. The mean age was 54 years and most patients were men (72%). In addition, 196 (35%) had surgery during the index hospitalization.

Results: 

The overall hospital mortality rate was 85 of 560 (15.2%). Sepsis (44%), heart failure (28%), and shock (19%) were the most common causes of death. The baseline characteristics that were more common in those patients who died included female sex (48% vs 36%, P < .05), gastrointestinal bleeding (15% vs 4%, P < .01), and prosthetic valve IE (29% vs 19%, P < .05). Intravenous drug use was more common in survivors (26% vs 15%, P < .05). The complications associated with death included major bleeding, heart failure, conduction disturbances, arrhythmia, and renal dysfunction (P < .01 for all). Treatment with surgery was associated with survival (37% vs 24%, P < .05). There were no organism differences between those patients who did and did not survive the initial hospitalization.

Interpretation: 

Overall, the MATIE study represents one of the largest groups of patients collected prospectively in North America with IE. The predictors of mortality were consistent with other data except that specific infecting organisms, such as Staphylococcus aureus, were not associated with mortality. It is interesting to note that, although the hospital mortality rate was consistent with data from other centers, the surgical treatment rate was higher than is generally seen in US hospitals. In addition, it is not clear which factors were independently associated with mortality. Large multicenter cohort studies are needed to more fully describe the clinical characteristics associated with mortality and to investigate which patients benefit most from aggressive surgical treatment.

Study: 

Expression of angiotension II receptors in human aortic valve lesions: a potential role of the renin-angiotensin system in the pathogenesis of aortic stenosis

Presenter: 

Dr David M. Shavelle, University of Washington, Seattle, Wash

Background: 

Lesions of aortic stenosis (AS) share many similarities with lesions of atherosclerosis. These include inflammatory cell infiltrates and lipoprotein deposition. Factors that are associated with coronary artery disease, such as hypercholesterolemia, are also associated with AS. It has been hypothesized that the renin-angiotensin system may play a role in the pathogenesis of atherosclerosis and may explain, in part, the reduction in adverse outcomes with angiotensin-converting enzyme inhibition (ACE-I) therapy. Previous work by this group has shown that ACE protein is present in human AS lesions and is associated with lipoprotein deposits. The current study was undertaken to determine whether receptors for angiotensin (AT) II were present in AS lesions.

Aortic valves were obtained from 21 patients at autopsy (n = 17) or at the time of valve replacement (n = 4). Immunohistochemistry was performed on the valve tissue to examine the tissue for AT-1 or AT-2 receptors.

Results: 

This analysis found that normal aortic valves did not contain AT-1 or AT-2 receptors, whereas these receptors were found within aortic valve lesions. AT-1 receptors were more common in the more diseased valves and AT-1 receptor concentration correlated with AS severity.

Interpretation: 

These findings imply that the renin-angiotensin system may be involved with the development or progression of aortic valve stenosis. Further studies are needed to verify these findings. In addition, this may provide an opportunity to test AT-1 receptor blockade and the effect on AS progression.

Study: 

The Pravastatin Inflammation/CRP Evaluation (PRINCE)

Presenter: 

Dr Paul M. Ridker, Brigham and Women’s Hospital, Boston, Mass

Background: 

C-reactive protein (CRP) is a sensitive acute-phase reactant whose levels increase in response to inflammation, infection, and tissue damage. High-sensitivity CRP (hs-CRP) assays have demonstrated predictive value for adverse cardiac outcomes in patients with known coronary disease. In a substudy of the Fragmin During Instability in Coronary Artery Disease (FRISC) trial, elevated hs-CRP was an independent risk factor for long-term cardiac death.1 Furthermore, baseline hs-CRP levels are associated with an increased risk of myocardial infarction (MI) and stroke among apparently healthy individuals.2 In a retrospective review, post-MI patients randomized to pravastatin had significantly reduced hs-CRP levels compared with standard therapy and placebo.3 The reduction in hs-CRP was independent of low-density lipoprotein (LDL) lowering. Therefore PRINCE was designed to prospectively examine the effect of pravastatin on reducing hs-CRP levels in 2 parallel patient populations, a primary prevention cohort (unknown vascular disease with LDL levels >130 mg/dL) and a secondary prevention cohort (known vascular disease), and to determine whether the reduction was independent of lowering LDL.

The secondary prevention cohort (n = 898) was treated with open-label pravastatin 40 mg per day. The primary prevention cohort was randomized to pravastatin 40 mg per day (n = 673) or placebo (n = 666). hs-CRP levels and lipid profiles were measured at baseline and at 12 and 24 weeks. Patients were considered for inclusion if they were older than 21 years and clinically stable. Patients were excluded if they received lipid-lowering drugs in the prior 6 months, had contraindications to statin therapy, or had conditions that would confound baseline hs-CRP levels (eg, untreated hypothyroidism, rheumatoid arthritis). The primary end point was 24-week hs-CRP and lipid levels.

Results: 

The secondary prevention cohort was older (69 years vs 57 years), had a higher incidence of diabetes (25% vs 10%), and had a lower baseline LDL level (124 mg/dL vs 142 mg/dL). Baseline hs-CRP levels were comparable across all groups. Changes in lipid profile were statistically significant. Compared with placebo, there was a 25% mean reduction in LDL and a 6% increase in high-density lipoprotein in the pravastatin treatment arms at 24 weeks. A significant and comparable reduction in hs-CRP was seen in the 2 pravastatin-treated cohorts at 24 weeks (Table I).

Table I. Reduction in hs-CRP in the 2 pravastatin-treated groups at 24 weeks

	Cohort	Baseline CRP (mg/dL)	24-wk hs-CRP (mg/dL)	P value
	Primary prevention (placebo)	0.2	0.19	.9
	Primary prevention (pravastatin)	0.2	0.16	<.001
	Secondary prevention (pravastatin)	0.26	0.23	<.001

Interpretation: 

These prospective data confirm the hs-CRP reduction in pravastatin-treated patients with coronary artery disease seen in the retrospective analysis of the Cholesterol and Recurrent Events (CARE) trial. Furthermore, a significant reduction in hs-CRP was demonstrated with pravastatin therapy in a primary prevention cohort. These “anti-inflammatory” effects were present at 12 weeks and were not related to LDL lowering. However, the clinical benefit of lowering hs-CRP with statin therapy is unclear. A substudy in the ongoing A-to-Z Trial, a study investigating the early use of simvastatin in patients who have an acute coronary syndrome, will address the clinical impact of this question as it relates to cardiovascular outcomes. Furthermore, the utility of statin therapy titration to hs-CRP levels in primary prevention is yet to be examined.

Study: 

Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy (TACTICS-TIMI 18)

Presenter: 

Dr William S. Weintraub, Emory University Hospital, Atlanta, Ga

Background: 

TACTICS-TIMI 18 randomized 2220 patients with a non-ST-elevation acute coronary syndrome (ACS) to an early invasive or early conservative strategy with a background therapy of aspirin, unfractionated heparin, and the glycoprotein IIb/IIIa inhibitor tirofiban. The early invasive arm demonstrated a significant reduction in the primary composite end point of death, myocardial infarction, or ACS rehospitalization at 6 months.1 In the Fragmin and Fast Revascularisation during Instability in Coronary Artery Disease (FRISC-II) trial, the invasive strategy cohort in a Scandinavian population of patients with ACS treated with the low-molecular-weight heparin dalteparin demonstrated a similar benefit.2 However, the cost implications of an invasive strategy were unknown. TACTICS-TIMI 18 was the first trial with contemporary non-ST ACS therapy designed to prospectively evaluate the costs associated with each management strategy. Additionally, a quality-of-life comparison was examined.

The 1722 patients enrolled in non–Veterans Affairs hospital sites were included in the analysis. Hospital costs (UB92 formulation), physician costs (DRG codes), outpatient costs (Medicare fee schedule), medication costs (average wholesale price), and indirect costs (lost wages estimation) were determined. The primary end point was total cost at 6 months. Secondary end points included initial hospitalization costs, 30-day costs, and quality-of-life data. The Seattle Angina Questionnaire was used in the quality-of-life assessment.

Results: 

Initial hospitalization costs were higher ($14,660 vs $12,667), but 6-month follow-up costs were lower ($6063 vs $7203) in the early invasive arm. Total costs at 6 months were $629 more ($20,616 vs $19,987) with early invasive management. This difference was not statistically significant. In a subgroup analysis, costs were higher in patients with elevated troponin levels, but no cost difference in the 2 strategies was found. A similar trend was seen in the diabetic patient subpopulation. No differences were observed in the quality-of-life index. Each strategy revealed improvement in angina scores at 6 months.

Interpretation: 

Patients treated with contemporary ACS management receive the greatest benefit when they are managed with an invasive strategy, and this benefit is attained with an insignificant increase in the 6-month cost. This cost analysis further strengthens the argument for treating high-risk patients with non-ST ACS with an early invasive strategy.

Study: 

Race- and sex-based differences in the utilization of lipid-lowering medications after acute myocardial infarction

Presenter: 

Dr Gregg C. Fonarow, UCLA Medical Center, Los Angeles, Calif

Background: 

Numerous studies have documented significant race and sex differences in the use of invasive cardiac procedures after acute myocardial infarction. However, few studies have examined race- and sex-based differences in the use of more prevalent and less costly medical therapies indicated in the management of acute myocardial infarction and shown to reduce morbidity and mortality. Recently Raithore et al examined 169,079 Medicare beneficiaries from the Cooperative Cardiovascular Project database and found significant underuse of aspirin and β-blockers among African Americans and significant underuse of aspirin alone among women in the peri–myocardial infarction period. Although some data exist on racial and sex differences in the use of aspirin and β-blockers, there are no data on race- or sex-based differences in the use of equally efficacious medical therapy with lipid-lowering agents.

The purpose of this study was to examine the influence of race and sex on the receipt of lipid-lowering therapy at the time of discharge after acute myocardial infarction. The cohort consisted of 138,001 patients participating in the National Registry of Myocardial Infarction 3 between June 1998 and June 1999.

Results: 

Patients receiving lipid-lowering therapy (n = 43,730) compared with those who did not receive lipid-lowering therapy (n = 94,271) were significantly younger (63 years vs 70 years), more of them were men (67% vs 58%), and more of them were white (94% vs 93%). Patients receiving lipid-lowering therapy more often had a history of hypercholesterolemia (59% vs 20%), coronary artery bypass grafting (48% vs 13%), and percutaneous transluminal coronary angioplasty (48% vs 29%), and had received treatment at a teaching hospital (19% vs 13%).

The lipid-lowering treatment rate overall was 32%. It was lower among women than men (27% vs 35%) and among African American versus white patients (29% vs 32%). Although African Americans were less likely than whites to receive lipid-lowering therapy after adjustment for baseline characteristics (relative risk [RR] 0.94, 95% confidence interval [CI] 0.89-0.99), women were not less likely than men to receive lipid-lowering therapy (RR 0.97, 95% CI 0.94-1.00).

Interpretation: 

This study was limited as a retrospective analysis and did not provide information on the class of lipid-lowering agents prescribed nor whether patients were placed on these therapies after discharge. However, it is further evidence showing that race and sex may influence physician decision making with the use of cost-effective medical therapy. This is particularly compelling considering that medical therapy does not lend itself to the same degree as invasive procedures to patient refusal. Further research is clearly needed to understand the disparities in the use of these agents as well as interventions needed to improve the low use of these agents overall with focused attention on those affected disproportionately worse.

Study: 

Protective effects of angiotensin-converting enzyme inhibitors in African American men with coronary artery disease

Presenter: 

Dr Vasilios Papademetriou, VA Medical Center and Georgetown University, Washington, DC

Background: 

Although early epidemiologic studies showed that angiotensin-converting enzyme (ACE) inhibitors alone do not exert a satisfactory blood pressure effect in mildly to moderately hypertensive African American patients, subsequent studies have shown that these agents are efficacious in African Americans when combined with low-dose diuretics. Furthermore, these agents have been shown to dramatically reduce morbidity and mortality in patients with coronary artery disease and congestive heart failure. Recently, the results of the African American Study of Kidney Disease and Hypertension (AASK) study provided, for the first time, evidence that ACE inhibitors were successful in preventing progression to renal failure, dialysis, and death compared with a calcium channel blocker, amlodipine. Yet despite these data and the lack of representation of African Americans in many past clinical trials, African American patients remain undertreated with ACE inhibitor therapy.

The purpose of this study was to retrospectively assess the efficacy of these agents among a cohort of African American men with coronary artery disease within a VA medical system. The primary end points included all-cause mortality and cardiac and cardiovascular mortality.

Results: 

There were 810 patients identified who were undergoing diagnostic cardiac catheterization. Of these patients, 237 (23%) received ACE inhibitor therapy (enalapril, captopril, or lisinopril) and 573 (71%) did not. All patients received adjunctive therapies including β-blockers, calcium channel antagonists, diuretics, and statins. Both groups were similar in age and had similar entry blood pressure measurements. Patients on ACE inhibitors, however, had significantly more diabetes (43% vs 28%) and hypertension (75% vs 64%), higher left ventricular mass index (166 vs 156), more congestive heart failure (27% vs 10%), lower ejection fraction (49% vs 58%), and more complex arrhythmias (22% vs 14%).

Over a period of approximately 10 years, 74 (31%) patients in the ACE inhibitor groups died compared with 212 (37%) in the no ACE inhibitor group. The cardiac mortality rate was 18% vs 26% in the ACE vs no ACE inhibitor groups, respectively. After adjustment for baseline differences between the 2 groups, patients in the no ACE inhibitor group had an 80% higher mortality than did those treated with ACE inhibitors (relative risk 1.8, 95% confidence interval 1.3-2.6).

Interpretation: 

This study was limited as a retrospective analysis; however, in light of the results of the recent AASK trial, this study provides further evidence for the beneficial effects of these agents among African American patients with coronary artery disease. Although more clinical trials are needed with adequate representation of African Americans to further investigate this issue, clearly ACE inhibitors should be used in this population.

Study: 

Is β-adrenergic blockade in African Americans and whites equally effective?

Presenter: 

Dr Aitya Samal, Ochsner Heart and Vascular Institute, New Orleans, La

Background: 

There are convincing data showing that neurohormonal attenuation with β-blockers is effective in reducing morbidity and mortality in patients with congestive heart failure (CHF) resulting from systolic dysfunction. Both the Metoprolol Randomised Intervention Trial in Congestive Heart Failure trial (MERIT-HF) and the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS) showed an overall significant improvements in ejection fraction (EF) and New York Heart Association (NYHA) class and reduction in mortality in patients with systolic heart failure treated with either metoprolol or carvedilol. However, these trials included very few African American patients, and recent results of the Beta Blocker Evaluation of Survival Trial (BEST) showed an adverse trend in 1-year mortality among African American patients treated with bucindolol. African American patients in the treatment group had a 30% mortality versus 24% in the placebo group (P = .097). This has led to speculation regarding the efficacy of these agents in all patients, particularly African American patients.

The purpose of this investigation was to retrospectively examine a racially diverse sample of patients with CHF and systolic dysfunction treated with various β-blocking agents. The primary variables assessed included patient age, race, pre and post β-blocker EF, and pre and post β-blocker NYHA class. They also assessed concomitant use of angiotensin-converting enzyme inhibitors and digoxin, which have been demonstrated to improve EF and NHYA class.

Results: 

There were 88 African American patients and 143 white patients. There were no significant differences between African American and white patients in baseline NYHA class, post-NYHA class, or pre- and post-EF. African American patients showed a significant improvement between pre- and post-NYHA class (2.5 vs 2.1, P < .005). African American patients also demonstrated a significant improvement between pre- and post-EF (24% vs 30%, P < .005). Similarly, white patients demonstrated significant improvements in pre- and post-NYHA class (2.3 vs 1.8, P < .005) and pre- and post-EF (26% vs 28%, P < .005). There were no differences in the use of angiotensin-converting enzyme inhibitors or the use of digoxin between African American and white patients.

Interpretation: 

Although this study was limited as a retrospective analysis with relatively few numbers of patients overall and did not include mortality data, it provides evidence that the benefits of β-adrenergic blockers observed overall in prior trials should be extrapolated to all patients, including African American patients. To date, there is no biologic premise to explain why these agents would differentially affect African Americans worse than whites. Until prospective data are available, we must rely on the observed benefits overall and retrospective analyses such as these, which demonstrate similar clinical benefit in both African American and white patients with systolic heart failure treated with β-blockers.

Study: 

MIRACLE: Multicenter InSynch Randomized Clinical Evaluation

Presenter: 

Dr William T. Abraham, University of Kentucky College of Medicine, Lexington, Ky

Background: 

Despite progress in the pharmacologic management of advanced heart failure, mortality and morbidity remain high. This fact has resulted in a continued search for novel therapies, including an increasing number of device-based interventions. Ventricular dyssynchrony, or poorly coordinated contraction of the left ventricle, has recently been identified as a potential therapeutic target in heart failure. Preliminary studies have suggested that cardiac resynchronization therapy (CRT) via atrial synchronous biventricular pacing can improve acute hemodynamics and ventricular function in selected patients.1, 2 The mechanism of this benefit appears to be multifactorial and may include reduction in paradoxical septal wall motion, prolongation of diastolic filling time, and reduction in mitral regurgitation.1

The MIRACLE trial was a double-blind randomized controlled trial designed to assess the efficacy of the InSynch pacing system (Medtronic, Minneapolis, Minn) on clinical end points in patients with stable New York Heart Association (NYHA) class III-IV heart failure. MIRACLE enrolled patients who had been on optimal drug therapy for 1 to 3 months before study entry, who had a QRS duration of 130 milliseconds, left ventricular (LV) ejection fraction 35%, and LV end-diastolic dimensions of 55 mm. Patients who were enrolled in the study underwent placement attempt of the InSynch device, and those who had successful placement (93%) were then randomized to CRT (n = 134) or no CRT (n = 132). Therapy was continued for 6 months. To maintain blinding, an unblinded third party (the implanting electrophysiologist) reviewed all electrocardiograms and performed all device-related interventions. The primary end points of the study were improvement in quality of life as assessed by the Minnesota Living with Heart Failure Questionnaire, improvement in NHYA functional class, and improvement in 6-minute walk time.

Results: 

Baseline characteristics were similar between the 2 treatment groups. The mean age was 63.5 years, 69% of patients were male, and 90% were white. A total of 91% of patients were in NYHA class III, and the mean QRS duration was 165 milliseconds with a mean LV end diastolic diameter of 69.5 mm. Twenty-two patients (13 in the control group and 9 in the CRT group) did not complete the study, leaving 119 evaluable patients in the control group and 125 in the CRT group.

All 3 primary end points showed significant improvement in the CRT group compared with controls. NYHA class improved by an average of 0.8 in the CRT group versus no change in the controls (P < .001). Sixty-nine percent of the CRT group improved at least 1 NYHA class versus 34% of the controls. Six-minute walk time improved 39 m at 6 months for the CRT group versus no significant change in the controls (P = .033). Both groups showed improvement in quality-of-life scores, indicative of a substantial placebo effect, but patients in the CRT group demonstrated a significantly greater improvement from baseline than did control patients.

Interpretation: 

The results from MIRACLE suggest that cardiac resynchronization therapy can result in both subjective and objective improvements in functional status in patients with stable moderate to severe heart failure who have marked QRS prolongation and ventricular enlargement. The impact of this therapy on other key clinical end points such as heart failure hospitalizations or mortality awaits further study. Additionally, it is unclear whether similar benefits will be seen in a broader group of patients with heart failure with less severe QRS prolongation or LV enlargement.

Study: 

RITZ-2: Randomized Intravenous TeZosentan Trial

Presenter: 

Dr Guillermo Torre-Amione, Baylor College of Medicine, Houston, Tex

Background: 

Heart failure is a clinical syndrome marked by neurohormonal derangement, which has led to standard treatment with angiotensin-converting enzyme inhibitors, β-blockers, and spironolactone. A variety of additional neurohormones are increasingly understood to play a role in the pathogenesis of heart failure. Among these is endothelin-1, a potent vasoconstrictor, which is elevated in patients with heart failure and exerts its effect through endothelin A (ETA) and endothelin B (ETB) receptors on vascular smooth muscle cells and endothelial cells, respectively. A variety of agents blocking ETA or both ETA and ETB are under investigation.1, 2 The RITZ clinical trials program is evaluating tezosentan, an intravenous dual endothelin receptor antagonist, in patients with a variety of acute heart failure syndromes.

The RITZ-2 trial tested 24-hour infusions of 2 doses of tezosentan versus placebo in patients hospitalized with acute heart failure. All patients required intravenous pharmacologic therapy and continuous hemodynamic monitoring, as well as having a cardiac index of <2.5 L/min/m2 and pulmonary capillary wedge pressure (PCWP) of > or < 15 mm Hg. Patients were excluded if they had systolic blood pressure <85 mm Hg, evidence of an acute coronary syndrome, or recent percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. Patients in the 50 mg per hour tezosentan arm received 25 mg per hour of tezosentan for 1 hour, followed by 50 mg per hour for 23 hours. Patients in the 100 mg per hour tezosentan arm received 25 mg per hour for 1 hour, 50 mg per hour for 2 hours, and 100 mg per hour for 22 hours. The primary end point of the study was change in cardiac index at 6 hours. Important secondary end points were the change in PCWP, improvements in dyspnea score, and the time to worsening heart failure or death.

Results: 

Baseline characteristics were similar among the 3 treatment groups. The mean ejection fraction was 23%, cardiac index was 1.9 L/min/m2, and PCWP was 25 mm Hg. Overall, hemodynamic effects were similar between the 50 mg per hour and 100 mg per hour tezosentan arms. Cardiac index improved significantly in both treatment groups compared with placebo (by 0.42 L/min/m2 in the 50 mg/h arm and by 0.41 L/min/m2 in the 100 mg/h arm, compared with 0.04 L/min/m2 in the placebo group; P < .0001). PCWP also decreased significantly in the treatment groups compared with placebo (by 4.5 mm Hg in the 50 mg/h arm and by 4.6 mm Hg in the 100 mg/h arm, compared with 0.6 mm Hg in the placebo group; P < .0001).

Given the similar hemodynamic effects, the active treatment arms were combined for the analysis of clinical end points. A statistically significant improvement in dyspnea scores was seen in patients treated with tezosentan versus placebo (P = .048). Additionally, there was a trend toward a decrease in the time to death or worsening heart failure in the tezosentan-treated patients over the 24 hours of treatment (P = .06). Although both tezosentan doses were accompanied by a decrease in systolic blood pressure, this was not associated with increases in heart rate. Adverse events were similar between the 50 mg per hour tezosentan dose and placebo with the exception of headache, whereas the 100 mg per hour dose was associated with increases in symptomatic hypotension and renal impairment compared with placebo.

Interpretation: 

On the basis of these data, the 50 mg per hour dose of tezosentan appears to have similar hemodynamic effects to the 100 mg per hour dose with a more favorable side effect profile. Although measured clinical end points appeared favorable, the history of hemodynamic end points in previous heart failure trials dictates that these positive hemodynamic results be interpreted with caution until larger trials with clinical and safety end points are completed. The larger RITZ-1 trial, which is testing the effects of the 50 mg per hour dosing on clinical end points in 670 patients with acute heart failure, will be of help in assessing the potential of this new acute heart failure therapy. The optimal patient selection and duration of therapy for this potentially exciting new class of drugs remains to be determined by future studies.

Study: 

Heart Outcomes Prevention Evaluation (HOPE) study economic analysis

Presenter: 

Dr Andre Lamy, McMaster University, Hamilton, Ontario, Canada

Background: 

It is hypothesized that evidence-based clinical practice in North America has changed significantly as a result of the Heart Outcomes Prevention Evaluation (HOPE) study. The economic implications of increasing angiotensin-converting enzyme (ACE) inhibitor use in the United States are therefore of considerable interest.

Results: 

The HOPE study showed that treatment of patients with high-risk coronary artery disease (n = 9279) with no left ventricular dysfunction or heart failure with the ACE inhibitor ramipril significantly reduced the incidence of myocardial infarction, stroke, or death from cardiovascular causes (relative risk 0.78, 95% confidence interval 0.70-0.86; P < .001). The economic evaluation, conducted from a Medicare perspective, included direct costs of hospitalization, procedures, and medications. Cost data were collected prospectively and were in 1999 United States Dispensary. An annual discount rate of 3% was used over the 4.6 years of follow-up. The significantly higher cost of ramipril compared with placebo ($1480 vs $103, P < .0001) was offset by the lower costs of both hospitalization ($2987 vs $3601, P < .0001) and revascularization ($3990 and $4740, P = .0011), resulting in no difference in the overall cost per patient in the 2 groups ($13,520 and $13,631, P = .73). The costs of nonstudy medications were similar in both groups.

Interpretation: 

On the basis of these data, ramipril appears to be a clinically and economically attractive new health technology associated with fewer adverse events and lower health care utilization costs.

Study: 

Metformin versus other oral agents: does the choice of discharge diabetic medications predict mortality? Results from a registry of 1428 diabetic patients.

Presenter: 

Dr Farangis Lavasani, LDS Hospital, Salt Lake City, Utah

Background: 

Diabetes has a negative influence on clinical prognosis among patients with coronary disease. The effect of the various currently available hypoglycemic medical therapies on major cardiovascular outcomes remains poorly understood. The objective of the current study was to evaluate the influence of diabetic medications, including metformin, thiazolidinediones, sulfonylureas, and insulin on long-term clinical outcomes.

Results: 

The study cohort included 1428 patients with diabetes undergoing cardiac catheterization at a single institution between 1994 and 2000 and documented to have significant coronary artery disease (CAD) (>70% stenosis in at least 1 major epicardial artery) who were followed up for long-term clinical outcomes. Mean follow-up was 2.5 years, and multivariable Cox regression analyses were performed to evaluate the influence of diabetes therapy at discharge on the rates of death or myocardial infarction (MI). Monotherapy with either sulfonylurea (hazard ratio [HR] 1.7, P = .051) or insulin (HR 3.1, P < .001) was an independent predictor of death compared with metformin alone. The rate of MI was not different between treatment groups. Thus treatment of diabetic patients with CAD with metformin was associated with improved survival compared with sulfonylureas or insulin. Choosing insulin sensitization therapy as first-line treatment in this population may therefore be advantageous, although this requires additional validation.

Interpretation: 

These findings support prior observations from the United Kingdom Prospective Diabetes Study (UKPDS) in a population with diabetes at somewhat lower cardiovascular risk that demonstrated the superiority of metformin over “insulin-providing” therapy (sulfonylureas and insulin). Whether these observations represent improved outcomes associated with insulin-sensitizing therapies (metformin, thiazolidinediones) compared with an insulin-providing strategy or are specifically related to improved outcomes associated with metformin remains unknown. There were too few patients treated with thiazolidinediones among the study population to draw any meaningful conclusions about that class of drugs.

Importantly, the Bypass Angioplasty Revascularization Investigation (BARI) 2D study, funded jointly by the National Heart, Lung, and Blood Institute and industry, is just getting under way and will evaluate in a randomized study the primary strategies of insulin-providing versus insulin-sensitizing therapy among diabetic patients with CAD. The results of that study will not be available for several years. In the interim, the data are accumulating to support an initial strategy of insulin sensitization in general and therapy with metformin specifically among diabetic patients at risk for cardiovascular disease.

Study: 

Does enrollment in a randomized clinical trial lead to higher costs for routine care?

Presenter: 

Dr J. Peter Weiss, Stanford University, Stanford, Calif

Background: 

Reimbursement for the routine care of patients enrolled in clinical trials has become a recent topic of controversy. The current study evaluated the incremental medical costs associated with participation in a recent randomized trial.

Results: 

With data from the Myocardial Infarction Triage and Intervention (MITI) study, index hospitalization costs were compared between patients enrolled in the trial versus those eligible but not enrolled. Univariable and multivariable analyses were performed. Trial and control patients were similar, with the exception of older age and a nonsignificant trend toward increased hospital survival in the control patients. In univariable analyses, trial patients had lower total hospital costs compared with controls ($9300 vs $14,200, P > .0001). Costs for trial patients remained lower after multivariable adjustment 0.82 (95% confidence interval 0.74-0.91). Thus this study found no evidence that participation in the MITI randomized clinical trial led to higher costs for routine care.

Interpretation: 

These observations are intriguing and appear to contradict the consensus that trial participation increases the cost of medical care. Given the surprising observation that trial participation was found to decrease costs, it is important to consider some of the limitations of the study. Perhaps the biggest, yet unavoidable, limitation is that the decision to participate in the trial was not randomized, and there may be important differences in the trial and registry cohorts that influenced medical costs. Although the investigators did find a significant difference after adjustment for a number of important covariates, the analyses could not adjust for unmeasured or unknown characteristics that might affect medical costs. The study was also limited by the use of only index hospitalization costs. This is particularly relevant because many trials require long-term follow-up, often with protocol-driven resource use and therefore incremental medical costs.

Interpretation: 

These and other limitations nothwithstanding, the results are provocative and encouraging for patients, the community of clinical trialists, and importantly for Medicare and third-party payers. Further systematic evaluation of the influence of trial participation on medical resource use and costs, especially among trials with longer term follow-up, should be the focus of future investigation.

Study: 

Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE)

Presenter: 

Dr Salim Yusuf, McMaster University, Hamilton, Ontario, Canada

Background: 

Although many antiplatelet and antithrombotic therapies exist for the acute management of patients with acute coronary syndromes (ACS), only one, aspirin, is used for long-term care. Long-term administration of clopidogrel, a thienopyridine derivative that selectively and irreversibly inhibits adenosine diphosphate (ADP)-dependent activation of the platelet, has previously been shown to be more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction (MI), or vascular death in patients with atherosclerotic vascular disease.1

The Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial was designed to test the efficacy and safety of clopidogrel, given in addition to aspirin, in patients with non-ST-segment elevation ACS. CURE randomized 12,562 patients with ACS within 24 hours of symptom onset to aspirin alone (daily dose 75 mg to 325 mg) or aspirin plus clopidogrel. Clopidogrel was given as a 300 mg loading dose followed by a regular long-term dose of 75 mg per day. Patients were followed up for 3 to 12 months, with a median follow-up of 9 months. The trial was conducted in 482 hospitals in 28 countries, with most patients recruited in Western Europe (approximately 5000) and Canada (approximately 2000 patients); almost 500 patients were recruited in the United States.

The primary end point of the study was the triple composite of cardiovascular death, MI, and stroke; the secondary end point included these outcomes plus refractory ischemia, defined as ongoing chest pain symptoms resistant to maximum medical therapy (severe ischemia) and requiring coronary revascularization within 24 hours. The main safety end point was bleeding, which was divided into major, including life-threatening bleeding episodes (intracerebral bleeding, bleeding resulting in hemodynamic compromise requiring intervention or requiring transfusion of >4 units of blood), and minor bleeding.

Results: 

Important baseline characteristics were equally distributed between the 2 groups. Female patients comprised almost 40% of the enrolled subjects and 75% of patients had unstable angina as their enrolling diagnosis. Cardiac markers were elevated at baseline in 25% of subjects and almost 95% had abnormal baseline electrocardiogram, predominantly T-wave inversion and ST-segment depression. The main efficacy results of the trial are displayed in Table II.

Table II. Primary and secondary end points and components of the composite end points in the aspirin alone and clopidogrel/aspirin combination treatment groups in the CURE trial

	Efficacy end point	Aspirin (%) (n = 6303)	Clopidogrel plus aspirin (%) (n = 6259)	Risk ratio	P value
	Primary composite	11.5	9.3	0.80	<.0001
	Cardiovascular death	5.4	5.1	0.92	NS
	MI	6.7	5.2	0.77	<.001
	Stroke	1.4	1.2	0.85	NS
	Noncardiovascular death	0.7	0.7	0.96	NS
	Secondary end point	19.0	16.7	0.80	<.001
	Refractory ischemia	9.4	8.8	0.93	NS
	Severe ischemia	5.0	3.8	0.76	<.001

NS, Not significant.

Table III. Bleeding events in the aspirin alone and clopidogrel/aspirin combination treatment groups in the CURE trial

	Safety end points	Aspirin (%) (n = 6303)	Clopidogrel + aspirin (%) (n = 6259)	Risk ratio	P value
	Major bleeding	2.7	3.6	1.3	.003
	Life-threatening bleeding	1.8	2.1	1.15	NS
	Minor bleeding	8.6	15.3	1.8	<.001
	Transfusions	2.2	2.8	1.3	.03

NS, Not significant.

Interpretation: 

In CURE, the largest ever study of patients with non-ST-elevation acute coronary syndromes, the early and continuing long-term administration of clopidogrel in addition to aspirin reduced the risk of cardiovascular death, MI, and stroke by 20% over and above therapy with aspirin alone. As such, it suggests a synergistic effect of the modes of action of clopidogrel and aspirin in these patients.

Study: 

Even mild renal insufficiency is associated with increased mortality after percutaneous coronary interventions

Presenters: 

Drs Peter B. Berger and Patricia J. M. Best, Mayo Clinic, Rochester, Minn

Background: 

The cardiovascular risk associated with advanced levels of renal insufficiency is well appreciate.1, 2 This session served to increase awareness that even mild renal insufficiency is associated with a poor outcome in patients with pre-existing cardiovascular disease. This session focused on outcomes after percutaneous coronary intervention (PCI).

Results: 

This presentation of data from the Mayo Clinic included an analysis of 5031 patients who underwent successful PCI between January 1994 and August 1999. Patients were categorized by estimated creatinine clearance levels (derived with the Cockcroft and Gault formula)3 into arbitrary levels of renal function, and survival curves were generated for each renal function group. A dose-effect of renal impairment on mortality was demonstrated and illustrated that even the mild renal insufficiency group had a doubling of death compared with those with normal renal function. In a multivariable analysis, the investigators demonstrated that compared with patients with a creatinine clearance of 90 mL/min, the relative risk (RR) of mortality over the first year of follow-up for patients with a creatinine clearance of 70 mL/min was 1.5 (1.3-1.6); for 50 mL/min, the RR was 2.3 (1.8-2.9); and for a creatinine clearance of 30 mL/min, the RR was 3.7 (2.5-5.5). Dialysis was associated with a striking RR of 8.9 (5.3-15.0). The increased risk was independent of diabetes mellitus and many other variables known to be associated with mortality after PCI. Kaplan-Meier curves displayed the results and illustrated the underappreciated risk of even mild levels of renal dysfunction on long-term mortality. Another striking observation was the fact that even after excluding patients receiving hemodialysis: 48% of the patients in this data set had levels of chronic kidney disease commensurate with at least some level of increased risk. These authors’ use of creatinine clearance rather than serum creatinine as a predictor is to be commended as it more accurately characterizes renal function and identifies even mild renal impairment as the cardiovascular risk factor it truly is. This presentation clearly elucidated the increase in risk of long-term mortality associated with chronic kidney disease in patients undergoing PCI.