	In the current edition of Cardiology Review, Gustafsson and colleagues (page 37) present their data on a large cohort of patients in Denmark who were screened for a study on the effect of the antiarrhythmia drug dofetilide (Tikosyn) on mortality in congestive heart failure (CHF). The effect of the drug was found to be neutral and, therefore, patients enrolled in the study and those screened but not enrolled were surveyed for the present analysis of mortality as a function of age.

	It is useful to note that these patients represent 5,548 consecutive patients hospitalized in Danish hospitals for new or worsening CHF between 1993 and 1996. So inclusive a population study, with its clear relevance to the population at large, would be difficult to carry out in the United States, or in any country with a fragmented health care system, in which the data are as fragmented as the care itself.

	The authors divided their cohort into the following age groups: less than 61 years, 61 to 70 years, 71 to 80 years, and more than 80 years. Follow-up was for 5 to 8 years. They examined multiple variables, as one would expect, including left ventricular size and function; presence of ischemic heart disease; hypertension; diabetes; smoking; atrial fibrillation; renal function; and duration of CHF. Of note, presence of anemia, a current subject of interest, was not investigated.  

	Age was a significant predictor for both short-term (30 days) and long-term mortality. As one would expect, left ventricular function was significantly associated with long-term survival for any age group (Table).

	Two questions naturally arise, particularly as one looks at the oldest age groups: How does survival in these CHF patients compare with survival in the general population? How long does one expect a 70-year-old, or an 80-year-old, to survive? Data from the Centers for Disease Control and Prevention (CDC) are of interest in this regard. Shown below the Table is the life expectancy for corresponding age groups in the general population, according to 2002 data from the CDC.

	It is clear that, even in the oldest age group, CHF represents a considerable burden on life expectancy. This sort of data should reinforce the demand that age not be an excuse for withholding optimal care because there are potential good years of life to be gained from successful treatment of the elderly.

	A number of other interesting findings emerge from the authors’ analysis. There were more women in the older age groups, their symptoms had been present for longer, and they had a much higher incidence of diastolic dysfunction. Not surprisingly, atrial fibrillation was more common in the older population. Interestingly, hypertension was not more prevalent in the older groups, and thus there is not, in these data, a good explanation for the higher incidence of diastolic dysfunction. This correlation of diastolic dysfunction with age is now well recognized, however, and may relate to other anatomic and physiologic changes in the myocardium.  

	What is the take-home message from this analysis? CHF has a major impact on life expectancy (with a startling 72% overall mortality during follow-up), and older patients have worse prognoses. Their prognosis is due to the CHF, however, and not to their age alone; therefore, we owe it to all such patients to offer optimal treatment (with due regard for their age).

Articles

Cardiology Review Online

Is mortality a function of age  in congestive heart failure? 

	An 83-year-old man with a history of hypertension and atypical chest pain on exertion was admitted to the hospital because of dyspnea. On clinical examination he had minor ankle edema and moderate pulmonary congestion. Cardiac auscultation revealed a discrete systolic murmur. The electrocardiogram showed a sinus rhythm and left ventricular (LV) hypertrophy with strain. An echocardiogram showed LV dilatation (LV end-diastolic diameter 69 mm); the LV ejection fraction was 15%. Minor mitral valve regurgitation was noted. A coronary angiogram revealed no significant coronary artery stenoses. After stabilization, he was referred to an out-patient, nurse-based heart failure management program, placed on an angiotensin-converting enzyme inhibitor, and started uptitration with a beta blocking agent.

	Heart failure education was pro-vided to the patient and his relatives, and exercise rehabilitation was offered but refused. Despite these measures he remained in New York Heart Association functional class III, and consequently spironolactone (Aldactone, Spironal) was added. The patient was discharged from the management program on optimal pharmacologic treatment and referred back to his primary care physician for follow-up.

	Spironolactone was stopped after 2 months due to serious hyperkalemia. The patient was reevaluated by a cardiologist. The echocardiogram showed an ejection fraction of 10% to 15% and moderate mitral valve regurgitation. The patient was still in sinus rhythm and QRS duration was less than 120 ms. It was concluded that drug therapy could probably not be further optimized and he was not a candidate for cardiac resynchronization therapy. He was not likely to benefit from mitral valve surgery, as regurgitation was only moderate. He was offered referral back to the nurse-led management program for another attempt at instituting spironolactone, but the patient was reluctant to travel to the clinic on a regular basis again. Because his expected life span was short (likely less than 1 year), the patient was supported in his decision to decline further aggressive interventions, and instead plans involving his family and primary care physician were made for home care and support. There comes a point at which palliation should be the objective of medical care.

Treatment of an 83-year-old man with congestive heart failure 

	Managing atrial fibrillation remains difficult. Treatment options include attempts to control the rhythm (to maintain sinus rhythm), attempts to control ventricular rate, and anticoagulation. The hope is to reduce thromboembolic complications, prevent hospitalization, improve quality of life and symptoms, and extend longevity. Ventricular rate control, a valid but challenging approach, can be used concurrently or in lieu of other management strategies.1,2

	Attempts to control the ventricular response rate to atrial fibrillation include treatment with a selection of drugs that has not changed for years. Drug classes include calcium channel blockers, beta blocking agents, and digoxin alone or in combination. Atrioventricular junction ablation with permanent pacemaker implantation is another possibility. Considering the magnitude of the problem of atrial fibrillation, the fact that the drugs used to control ventricular response rate have not changed in years, and the importance of controlling rate, one may suspect that extensive data document a best approach to controlling the rate; however, data are lacking.

	Farshi and colleagues evaluated patients with chronic atrial fibrillation in whom the ventricular rate was assessed at rest, with exercise, and during daily activities.3 This study evaluated a beta blocker, a calcium channel blocker, and digoxin. The best approach was combining a beta blocker and digoxin to control the rate at rest and with exercise. This study, consisting of 12 patients, did not compare specific drugs in any one class or test a spectrum of drug dosages. The end points related to patient outcomes remain unknown. The results of this study and other small clinical trials may not be applicable to most patients with atrial fibrillation.4-7

	Atrioventricular junction ablation, with or without pacing, particularly biventricular pacing, is not without its risks. This approach is used for patients whose rate is difficult to control, not for the average patient with atrial fibrillation.8-10 With this approach, sudden arrhythmic death can occur, especially when initial slower pacing rates < 80 beats per minute are selected, at least initially.11 Lead dislodgement and pacing complications can also arise.

	The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, a large, multicenter, randomized, controlled, clinical trial sponsored by the National Institutes of Health, compared rate control with rhythm control in elderly patients with atrial fibrillation who were at risk for stroke and who required anticoagulation.1 The purpose was to compare outcomes, particularly death, based on therapeutic approach.

	Results of a substudy of the AFFIRM trial including data on 2,027 patients randomized to the rate control arm and followed for an average of 3.5 years have also been reported.12 The methodology used to assess adequate rate control was strict.12 An average resting rate of ≤ 80 beats per minute and a rate ≤ 110 beats per minute during a 6-minute walk test, or an average heart rate of ≤ 100 beats per minute on 24-hour ambulatory monitoring with no heart rate over 110% of the maximum predicted age-adjusted exercise heart rate was considered adequate.

	The physicians at each enrolling site could use any standard rate-controlling option. Based on this approach, the rate control arm fared at least as well as the rhythm control group, if not

	better, in every measure. In the rate control arm, the mean age was 69.8 years and 40.6% of subjects were women.12 The primary diagnosis was hypertension in 51.6%, congestive heart failure was present in 23.4%, and 68.6% had normal left ventricular ejection fractions.

	In a multivariate model, gender, history of coronary artery disease (CAD), pulmonary disease, congestive heart failure, and hypertension predicted drug class. Beta blocker use was greater in patients with CAD, and use of calcium channel blockers was greater for women and those with pulmonary disease. Digoxin use was more common in patients with cardiomyopathy and nonwhites.12

	Initial rate control was achieved at rest with a beta blocker (with or without digoxin) in 75% of patients, with digoxin alone in 68%, and with a calcium channel blocker (with or with-

	out digoxin) in 66%.12 Rate control was also achieved during exercise using the same drugs. Not surprisingly, beta blockers effectively controlled rate with exercise. Surprisingly, digoxin alone was associated with adequate rate control in many patients with and without exertion.

	Allowing for drug switches, rate control could be adequately achieved in most patients. Drug switches occurred commonly (in 37% of patients) and may have been needed to control ventricular rate.12 At 5 years, about 80% of patients had successful rate control with and without exertion. More patients were switched to beta blockers than vice versa (P < .001).

	Use of calcium channel blockers remained unchanged in 56% of patients and digoxin use remained the same in 42%. Only a minority (108 patients) underwent atrioventricular junction ablation and implantation of a permanent pacemaker, and 147 other patients required a pacemaker for symptomatic bradycardia.

	From these data, it became clear that rate control with drug therapy is achievable at rest and with exercise, with a low incidence of side effects in most patients with atrial fibrillation, but that over time, beta blocker use increases. Drug combinations, such as a beta blocker and digoxin, were effective and few patients required atrioventricular junction ablation with a pacemaker. Drug selection must also be based on other underlying medical conditions, such as hypertension, heart failure, and CAD.

	There is still much to be learned about optimal rate control in atrial fibrillation. The best end point for optimal rate control at rest and during exercise is not clear. The efficacy of the different rate-controlling drugs to help maintain sinus rhythm is not known. Furthermore, drugs that control rate may not reduce symptoms or change other outcomes, such as mortality, hospitalization, heart failure, and ischemia.

	It is unknown whether a strict rate control approach or any rate control approach is even necessary or beneficial. A more lenient approach to rate control may provide the same outcomes with less effort. Standard clinical practice in which a drug is used to control rate does not employ Holter monitoring and/or a 6-minute walk test. Are these needed?

	With respect to this question, a study is under way comparing the AFFIRM study with the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) trial2 regarding outcomes in the rate control groups. A more lenient approach to controlling rate in atrial fibrillation was taken in the RACE trial compared with the AFFIRM study.1,2

	It is possible that, in time, pharmacological approaches will be perfected to control ventricular rate in atrial fibrillation better than current treatments. It is also possible that an alternative method of treating atrial fib-

	rillation, such as ablation to cure the problem, may be associated with superior outcomes. Until studies demonstrate a better method to treat elderly patients with atrial fibrillation at risk for stroke, standard medical therapy to control the ventricular rate, at standard doses, can provide acceptable treatment. As long as proper anticoagulation is prescribed, the outcomes are acceptable in the majority of patients and, perhaps, even superior to those achieved by attempts to maintain sinus rhythm.

Rate control in atrial fibrillation 

	Congestive heart failure (CHF) is a disease of the elderly, and the prevalence and incidence of CHF increases steeply with age.1 Given the demographics in the Western world, the population of elderly persons with CHF is rapidly increasing. Some previous studies have shown that age is an important negative prognostic factor in CHF,2,3 but others, even large studies, have not documented any effect of age on mortality.4-7 Several of these studies examined highly selected groups of patients, such as patients referred for transplant evaluation. Thus, it is not entirely clear whether age affects mortality in more unselected CHF populations. Furthermore, few previous studies have been dedicated to studying the effect of age in CHF and therefore little information is available about how advancing age modulates the effects of known risk factors in CHF. This information is of interest since several clinical parameters differ greatly among young and old patients with CHF. In particular, heart failure with preserved left ventricular systolic function (LVSF) is much more common in the elderly.8  

	The aim of the present study was to determine (1) if advanced age is a predictor of mortality in CHF, and (2) if age interacts with known predictors of risk in CHF, particularly LVSF.

	The study population consisted of patients screened for entry into the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND)-CHF study, which was a multicenter, randomized, double-blind, placebo-controlled trial of the efficacy of the class III antiarrhythmic agent dofetilide (Tikosyn) on mortality in patients with CHF. The drug trial included 27% of the screened population with CHF and showed no significant effect of dofetilide when compared with placebo9; consequently the current study did not distinguish between patients randomized or not randomized in the study.

	A total of 5,548 consecutive patients hospitalized in 34 Danish hospitals with new or worsening CHF were screened for entry into the trial between November 1993 and July 1996; these patients comprise the DIAMOND-CHF screening registry. Patients with acute myocardial infarction (MI) within the preceding 7 days were excluded. At screening, a clinical history and a physical examination were performed together with a standardized echocardiogram. LVSF was assessed by calculation of wall motion index (WMI). An estimate of ejection fraction can be obtained by multiplying WMI by 0.3. Significant left ventricular systolic dysfunction was defined as WMI < 1.2 (LVEF approximately below 0.35).

	Survival status was provided by the Danish Central Personal Registry in the fall of 2002, resulting in a follow-up time of 5 to 8 years. Survival status was available on 5,491 patients. The study was approved by the Central Danish Ethics Committee.

	Differences in time to death between groups were analyzed by a two-sided log-rank test. Relative risks (RR) and 95% confidence intervals were calculated as hazard ratios obtained from Cox proportional-hazard models.

	Baseline characteristics of the 5,491 patients are given in Table 1. Mean age was 71.7 ± 10.2 years with 13% being younger than 61 years, 27% between 61 and 70 years, 40% between 71 and 80 years, and 20% aged 81 or older. Younger patients were more commonly male. The prevalence of previous MI increased with age until the age group older than 80 years, in which the prevalence of ischemia declined and a similar trend was seen for several baseline

	risk factors (hypertension, diabetes, and chronic obstructive pulmonary disease [COPD]). The degree of LV systolic dysfunction was greater in the younger patients. Elderly patients were less frequently treated with angiotensin-converting enzyme (ACE) inhibitors. This was true also when the analysis was restricted to those patients with significant LV dysfunction where ACE inhibition was clearly indicated (WMI ≤ 1.2). In the group of patients younger than 60 years, 84% were receiving an ACE inhibitor versus 60% of the patients older than 80 years (P < .001). Few patients were treated with beta blocking agents. Thirty days after the  index hospitalization, 5% of the patients had died, ranging from 3% in the youngest patients to 10% in the oldest (Table 1).

	A 10-year increase in age resulted in a highly significant increase in risk of death within the first 30 days (RR, 1.55 [1.36—1.76], univariate analysis). In a multivariate analysis containing age, sex, WMI, left ventricular end- diastolic diameter (LVEDD), history of ischemic heart disease or MI, COPD, diabetes, hypertension, valve disease, atrial fibrillation, smoking, creatinine clearance, and duration of heart failure, age was independently associated with 30-day mortality (RR per 10-year increase, 1.23 [1.04–1.47, P = .02]).

	During the entire follow-up period, a total of 3,955 patients (72%) died. The risk ratio for death during long-term follow-up associated with a

	10-year increase in age was 1.55 (1.50—1.61, P < .001, Figure 1). In a multivariate analysis similar to the

	one described for short-term out-come, age interacted significantly with WMI (P = .003) and thus separate multivariate models were generated for patients with LV systolic dysfunction (WMI ≤ 1.2) and those with WMI greater than 1.2. Age was a significant predictor of mortality in both models. For patients with LV systolic dysfunction, the RR (10-year increase in age) was 1.29 (1.19—1.39) and for patients with WMI greater than 1.2 the RR was 1.57 (1.43–1.72). Adding the presence or absence of treatment with diuretics, beta blockers, ACE inhibitors, or digoxin at discharge to the multivariate model did not significantly alter the RR for the effect of age (data not shown). To give a more clinically useful impression of what to expect in terms of survival for hospitalized CHF patients, the median survival time was calculated for the various age groups (Table 2). Figures for the patients younger than 60 years should be interpreted with caution, because less than 50% in this group had died at follow-up.

	This study confirms that older patients are more likely to be female and less likely to have LV systolic dysfunction and dilatation.1,10,11 The presence of risk factors and comorbidity was clearly dependent on age, but the association was not linear. Similar results regarding the distribution of hypertension, ischemic heart disease, and diabetes have been reported from a study in the Digitalis Investigation Group (DIG) population. There is no simple explanation for the apparent decline in hypertension, diabetes, and ischemic heart disease in the oldest patient group. It could relate to underdiagnosis of these comorbidities or to a selection process implying that patients with these conditions simply were less likely to survive until the

	age of 80 or older. The proportion of elderly patients being treated with ACE inhibitors was considerably lower than in the younger patients, even after controlling for the difference in the proportion of patients with LV systolic dysfunction. Lower use of ACE inhibitors in elderly CHF patients has been reported previously10,12 and may be related to a higher frequency of contraindications or fear of adverse effects in the geriatric pop-ulation. The study does not provide useful information about beta blockade in the elderly because patients were included in the registry several years before the general recommendation for beta blocker use in systolic heart failure.

	The present study shows that advancing age increases short- and long-term mortality in hospitalized heart failure patients. The effect of age on mortality was substantial and persisted after controlling for several potential confounders. Most previous studies have reported increased mortality with advancing age.2,13,14 In a number of studies, however, no effect of age on mortality has been found. A complex effect of age was reported from the large Department of Veterans Affairs Cooperative Vasodilator-Heart Failure Trials (V-HeFT) database.4 Even though a small effect of age on mortality was detected in V-HeFT-I, no effect was found in V-HeFT-II and consequently there was no overall independent effect of advancing age.

	Possibly the absence of an effect of age in the V-HeFT study could be explained by the fact that only men aged 75 years and younger were included. Similarly, other studies in which no effect of age has been found may have been undersized or may have included mainly younger patients, reducing the chance of discovering an effect.5-7 Indeed, some studies have demonstrated an effect of age only in the oldest patients.15 In our study, an effect of age could be demonstrated in all age strata. Overall, it seems reasonable to conclude that in studies that do not exclude elderly patients (either by age per se or by criteria correlating with advanced age), increasing age appears to have a clear negative impact on survival in patients with CHF. This effect appears to be greater in patients with preserved LVSF. The reason for this interaction is not clear. However, since normal LVSF is a predictor of survival, it could be speculated that in patients with preserved LVSF, the aging process, and the cardiac and noncardiac diseases associated with it, might play a greater role.  

	Elderly patients are undertreated with ACE inhibitors. Although age appears to be of greater importance in patients with nonsystolic heart failure than in those with low ejection fraction, advancing age is a potent, independent risk factor for short- and long-term mortality in all hospitalized CHF patients.

Age and mortality in congestive heart failure

	There is increasing evidence that in the setting of an acute coronary syndrome (ACS), early therapy with HMG-CoA reductase inhibitors (statins) may be beneficial. Trials such as the Scandinavian Simvastatin Survival Study (4S), the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID), and the Cholesterol and Recurrent Events (CARE) trial helped to establish the role of statins as essential therapeutic agents in the secondary prevention of cardiovascular disease (independent of baseline cholesterol levels).1-3 The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial examined treatment in the period immediately after an ACS and showed that early statin therapy reduced the recurrence of symptomatic myocardial ischemia.4 Subset analysis showed that early statin therapy reduced the circulating levels of C-reactive protein (CRP) and serum amyloid A.

	CRP has been shown to have numerous proinflammatory properties and so reduction in CRP was postulated to not only be a marker of reduced inflammation but rather evidence that statins may serve to attenuate potential direct inflammatory triggers.5,6 Other studies have shown that early statin therapy not only resulted in event-free survival benefits but also increased minimal luminal diameter as seen in quantitative angiography.7

	In this study, Okazaki and colleagues (page 29) aim to show that early statin therapy after ACS would induce a significant reduction in plaque volume in nonpercutaneous coronary intervention (non-PCI) sites. They postulate that the anti-inflammatory properties of statins reduce plaque volume, increase luminal diameters of coronaries, and therefore may confer protection from recurrence of cardiovascular events. In this prospective, open-label, randomized, single-center study, the investigators randomly assigned 70 patients to either atorvastatin (Lipitor) 20 mg orally once daily or a lipid-lowering diet (a cholesterol absorption inhibitor was added to the control group if low-density lipoprotein [LDL] cholesterol was greater than 150 mg/dL after initiation of the diet) 24 hours after PCI and intravascular ultrasound (IVUS) measurements were completed for ACS. The target segment for these IVUS measurements was determined in a non-PCI site, and vessels with marked tortuosity or calcifications were excluded. An inves-tigator blinded to patient group and angiographic results performed quantitative analysis. At the completion

	of the study, 48 patients (24 in each group) were analyzed (most patients were excluded due to marked tor-

	tuosity or calcifications in the target vessels). At the 6-month follow-up

	the results showed that the plaque volume was reduced significantly (13.1 ± 12.8%) in the atorvastatin group and increased in the control group (8.7 ± 14.9%) with the difference reaching statistical significance (P < .001). They also showed that the reduction in plaque volume had a significant positive correlation with follow-up reduction in LDL levels. Major adverse coronary events did not differ between the two groups.

	While the authors acknowledge that their study is limited by a small sample size, they do not address that the study lost over a third of its participants before analysis. It is unclear whether the final 48 subjects were matched at baseline. Furthermore, the selection of the target vessel for serial measurements was nonstandardized and left to the discretion of the nonblinded operator during the PCI. Despite its limitations, the study does highlight the importance of early statin therapy after ACS.

	Questions left to be answered include the following: Independent of LDL levels, what does the reduction of plaque volume mean in terms of clinical significance? Are the reduced plaques in fact more stable, and (again independent of LDL levels) do they confer protection to the patient? Nonetheless, these findings imply that patients with ACS are in a unique position to have the burden of their disease ameliorated through statin therapy. It remains unclear if early statin therapy alleviates impaired endothelial activity, reduces overall inflammation, or acts through an antithrombotic pathway, but clearly this treatment is beneficial and should be considered early in all patients with ACS.

Early statin therapy in ACS: Reducing the burden

	These figures show a representative case from each group in the ESTABLISH study. Baseline and follow-up IVUS images in both groups are presented; follow-up IVUS images are shown below the baseline images. Marked enlargement of the lumen and a decrease of plaque are clearly observed in the patient treated with atorvastatin at the non-PCI site after only 6 months of aggressive lipid-lowering therapy, whereas a significant reduction of the lumen and an increase of plaque are observed in the control patient.

Representative cases from the ESTABLISH study

	In large clinical trials, therapy with HMG-CoA reductase inhibitors (statins) has been shown to prevent recurrent coronary events in patients with coronary artery disease.1-3 Recent clinical trials have also shown that early treatment with statins could reduce recurrent coronary events after onset of acute coronary syndrome (ACS), even during the immediate follow-up period.4,5 Although the pleiotropic effects, such as anti-inflammatory effects and improvement of endothelial function, were suggested in these trials, the means by which improvement occurred was not clear. The reduction in low-density lipoprotein (LDL) cholesterol levels did indeed correlate well with event reduction in some clinical studies.

	To determine whether early LDL cholesterol—lowering therapy (within 24 hours of emergency percutaneous coronary intervention [PCI]) with atorvastatin (Lipitor) could result in a marked decrease in plaque volume as shown on volumetric intravascular ultrasound (IVUS) analysis, we conducted an open-label prospective study. We also examined whether the percent change in plaque volume correlated with the percent of LDL cholesterol reduction.

	In the Early Statin Treatment in patients with Acute coronary syndrome: Demonstration of the Beneficial effect on atherosclerotic Lesions by Serial volumetric Intravascular ultrasound Analysis during Half a year after coronary event (ESTABLISH) study, 70 patients were randomly assigned after PCI either to a control group or to an atorvastatin treatment group. To control for diabetes mellitus, total cholesterol level at baseline, culprit vessel, and sex, minimization methods were used. The study included ACS patients with severe stenosis as shown on coronary angiography (CAG) who had received PCI and who had undergone IVUS examination. Patients who were given certain other lipid-lowering drugs, who had cardiogenic shock, who were referred for coronary artery bypass graft surgery, or who had unsuccessful PCI were excluded from the study. Those in the atorvastatin group (n = 35) received 20 mg of atorvastatin once daily within 24 hours after emergency PCI. Patients in the control group (n = 35) were given usual care, which consisted of following a diet designed to reduce lipids and, for those whose LDL cholesterol levels did not decrease to less than 150 mg/dL, a cholesterol absorption inhibitor was prescribed for ethical reasons.

	IVUS images were obtained at the start of the study and after 6 months. Changes in plaque volume of one target point in a nonculprit lesion were compared between the two groups during the 6-month follow-up period. The primary end point of the study was

	the change in plaque volume measured by volumetric IVUS analysis. The secondary end point was the association between the percent change in LDL cholesterol level and plaque volume. Continuous variables were analyzed using the Mann-Whitney rank sum test or unpaired Student’s t test. The chi-square test was used to analyze the differences in categorical variables between the two groups. Linear regression analysis was used to assess associations. The Kaplan-Meier method was used to evaluate event-free survival. A probability value of less than .05 was considered to indicate statistical significance.

	Baseline and follow-up IVUS examinations were performed using the same equipment for both groups. Following intracoronary injection of 0.2 mg of nitroglycerin, the ultrasound catheter was placed 10 mm distal to the PCI location. At a speed of 0.5 mm/sec, auto-pullback was performed. S-VHS videotape was used to document the results of the IVUS examination. Quantitative analysis was performed by individuals at our IVUS laboratory. One target segment was selected in each patient more than 5 mm from the PCI site. The target segment was required to have a reproducible index side branch. To achieve accurate an-alysis, we did not use vessels that

	were tortuous or significantly calcified.

	The Netra volumetric analysis system (ScImage) was used to analyze the plaque volume. This system provides 100 cross-sectional sliced images that permit analysis of a 10-mm length of plaque. The plaque volume is calculated from these 100 sliced images using Simpson’s method. All volumetric analyses were evaluated by an experienced independent IVUS observer unaware of the patient’s group and angiographic data.

	A total of 35 patients were enrolled in the control group and 35 were enrolled in the atorvastatin group. As shown in Table 1, the two groups were similar with regard to baseline data, procedural characteristics, and lesion attributes. Because they refused follow-up CAG, two patients in the atorva-statin group were withdrawn from the study. Three patients in the control group did not complete the study: one refused follow-up CAG, one moved to another location, and one died of noncardiac causes. The 65 remaining patients received follow-up IVUS and CAG evaluation. Of these, 17 patients were excluded because of poor-quality IVUS images that could not provide for accurate analysis. We therefore analyzed IVUS images for 24 patients in each group.

	As shown in Table 2, the LDL cholesterol level was markedly reduced in the atorvastatin group compared with the control group, which showed an increase in LDL level (47.1% reduction for the atorvastatin group versus 0.7% increase for the control group). Plaque volume was also markedly decreased in the atorvastatin group compared with baseline measurements (69.6 ± 49.0 mm3 at baseline versus 61.4 ± 44.9 mm3 at 6 months; P < .001), with an average reduction of 13.1%. There was an increase in plaque volume, however, in the control group (59.5 ± 38.6 mm3 at baseline versus 63.7 ± 40.1 mm3 at 6 months; P = .0276), with an average increase of 8.7% (P < .001 for the atorvastatin group versus the control group at follow-up). The lumen volume was also increased by an average of 5.8% in the atorvastatin group.

	No matter what the baseline LDL cholesterol level was, there was a marked association between the percent LDL cholesterol level reduction and the percent change in plaque volume. As shown in Figure 1, in the atorvastatin group, there was no association between percent change in plaque volume and baseline LDL cholesterol level (R = 0.154), but the percent change in plaque volume was positively associated with the LDL cholesterol level at follow-up (R = 0.456; P = .001). As shown in Figure 2, although there was no association between the percent change in plaque volume and the percent gain in high-density lipoprotein cholesterol level (R = 0.206), the percent change in plaque volume was positively associated with the percent LDL cholesterol reduction (R = 0.612; P < .001). Figure 3 shows that, after dividing patients into two groups based on the median LDL cholesterol level

	(> 125 mg/dL and < 125 mg/dL), both groups showed a similar significant positive correlation between the percent change in plaque volume and percent LDL cholesterol reduction (R = 0.685, P < .001 in patients with baseline LDL cholesterol < 125 mg/dL; R = 0.462, P = .023 in patients with baseline LDL cholesterol > 125 mg/dL).

	Cardiac events in both groups were similar; 25.0% of patients in the control group and 24.2% of patients in the atorvastatin group had target-vessel revascularization.

	Significant plaque regression by intensive lipid-lowering therapy with a statin had not previously been shown using volumetric IVUS analysis. In this study, plaque regression was evident with only 6 months of pharmacologic intervention after onset of ACS. The percent change in plaque volume was also strongly associated with the LDL cholesterol level at 6 months and percent LDL cholesterol reduction, no matter what the baseline LDL cholesterol level was. Plaque regression was not shown after 12 months of follow-up in some studies.6,7 We think this occurred because of differences in the conditions and populations in each study. The German Atorvastatin Intravascular Ultrasound (GAIN) study and Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study were designed for patients with stable coronary artery disease, whereas our study populations were ACS patients. In the recent pathological studies, as well as clinical studies using CAG, intravascular angioscopy, and IVUS, ACS patients usually had multiple vulnerable plaques.8-12 These studies suggest that coronary plaques are prone to regress with intensive statin treatment in patients with ACS. We speculate that the plaque regression seen in our study was related to the stabilization of vulnerable plaque in the nonculprit lesion as a result of aggressive LDL-lowering in patients with ACS.

	The results of our study showed that intensive early therapy with atorvastatin could reduce the plaque volume in patients following the appearance of ACS. The beneficial effect of atorvastatin was evident whether patients had a high baseline LDL cholesterol level (> 125 mg/dL) or not, indicating that this lipid-lowering therapy would achieve favorable results for patients with ACS no matter what their LDL cholesterol levels were. This efficacy can be an important mechanism for event reduction using early statin treatment in ACS patients.

Is early statin therapy effective in the acute coronary syndrome? 

	Pulmonary arterial hypertension (PAH) is a complex disease state that can be difficult to diagnose accurately and to treat effectively. It is defined as a sustained increase in pulmonary arterial pressure to more than 25 mm Hg at rest or to more than 30 mm Hg with exercise, with a mean pulmonary capillary wedge pressure and left ventricular end-diastolic pressure of less than 15 mm Hg.1 PAH has an estimated prevalence of 30 to 50 cases per million, and idiopathic pulmonary hypertension has an incidence rate of one to two cases per million per year.2

	In 2003, the World Health Organization reclassified pulmonary hypertension into five broad categories: (1) pulmonary hypertension, including idiopathic (primary) pulmonary hypertension; (2) pulmonary hypertension involving the left side of the heart; (3) pulmonary hypertension associated with hypoxemia or chronic obstructive pulmonary disease; (4) pulmonary hypertension as a result of chronic thrombotic disease, embolic disease, or both; and (5) miscellaneous (pulmonary hypertension associated with sarcoidosis, Langerhans cell histiocytosis, or compression of pulmonary vessels). Vasoconstriction, remodeling of the pulmonary vessel wall, and thrombosis in situ are thought to cause the increased pulmonary vascular resistance that characterizes this disease.3 Endothelial dysfunction is also a culprit. These findings suggest that perturbations in the normal relationships between vasodilators and vasoconstrictors (endothelin-1), between growth inhibitors and mitogenic factors, and between antithrombotic and prothrombotic determinants are present.4

	In addition to these intrinsic determinants, there are three associated environmental factors that have strong associations with the development of PAH. Hypoxia induces vasodilation in systemic vessels but induces vasoconstriction in the pulmonary vasculature.4 Anorexogens have been associated with the development of PAH since the 1960s. The most recent culprits are fenfluramine (Pondimin) and dexfenfluramine (Redux), which were developed in the 1980s. It has been noted that an increase in pulmonary pressure can occur after as little as 3 to 4 weeks of exposure to these agents.4 Central nervous system stimulants, such as cocaine and methamphetamine, have also been associated with an increased risk of PAH. An autopsy study of 20 heavy cocaine users showed that the lungs of four of them had medial hypertrophy of the pulmonary arteries without evidence of foreign body embolization.4

	Several coexisting conditions have been associated with an increased propensity toward PAH. Connective tissue disorders have a high correlation with PAH. Diffuse scleroderma is associated with PAH in as many as one third of patients, and limited scleroderma (CREST syndrome [calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telan-giectasia]) occurs in as many as 50% of patients with PAH. Patients with systemic lupus erythematosus also have PAH, although less commonly than those with scleroderma.5

	Human immunodeficiency virus (HIV) infection and its association with PAH is well documented, although the mechanisms remain unclear.5 The cumulative incidence of PAH was 0.6% in a cohort of HIV-infected patients, a rate 6 to 12 times as high as in the general population. PAH was diagnosed in all stages of HIV infection without a relationship to CD4 cell count, but it appears to be related to the duration of infection.4

	There is an uncommon association between portal hypertension and PAH. Hemodynamic studies have found PAH in 2% to 5% of patients with cirrhosis; the prevalence may be higher (3.5% to 8.5%) in patients referred for liver transplantation.4 Certain hemoglobinopathies have a high concurrence with PAH. In patients with sickle cell anemia, the estimated incidence of PAH as shown by echocardiography varies between 8% and 30%. Recent studies have confirmed that PAH increases the risk of death in patients with sickle cell disease.4

	A diagnosis of PAH should be considered in patients who present with breathlessness in the absence of overt signs of specific heart or lung disease. Other symptoms of PAH can include fatigue, weakness, angina, syncope, and abdominal distention. The presence of these symptoms at rest is reported only in very advanced cases.6 One of the initial physical findings is the increased intensity of the P2 heart sound. Auscultation may reveal a systolic ejection murmur.

	A large a wave in the jugular venous pulse may occur due to reduced compliance of the hypertrophied right ventricle. A left parasternal (right ventricular) heave may be noted. Late findings in PAH include hepatomegaly, peripheral edema, and ascites, which are signs of right ventricular failure.5

	Severe PAH may be associated with prominent v waves in the jugular venous pulse as a result of tricuspid regurgitation, and an S3 may possibly be pres-

	ent. Uncommonly, the left laryngeal nerve may become paralyzed as a consequence of compression by a dilated pulmonary artery (Ortner’s syndrome).5

	Confirmation of PAH requires certain diagnostic tests. The electrocardiogram (ECG) may provide evidence suggestive of PAH. It may show right ventricular hypertrophy or strain. Findings of chronic right ventricular overload, such as right axis deviation and incomplete or complete right bundle branch block, may also be present. However, the ECG does not have sufficient sensitivity (55%) and specificity (70%) to be a screening tool for detecting significant PAH.6 The classic chest radiograph may show central pulmonary arterial dilation and loss (pruning) of peripheral blood vessels in patients with PAH. In later disease, there may be right ventricular and right atrial dilatation.

	Transthoracic echocardiography (TTE) is an excellent noninvasive screening test for the patient suspected of having PAH. TTE usually shows enlargement of the right atrium and ventricle with normal or small left ventricular dimensions.5 Abnormal ventricular septal motion as a result of right ventricular volume and pressure overload is characteristic.5

	Doppler echocardiographic quantitation of pulmonary artery pressure can be obtained by measuring the maximum velocity (Vmax) of the tricuspid regurgitant jet and by using the Bernoulli formula (P = 4V2), where P = pressure and V = velocity. Doppler echocardiography sometimes overestimates the pulmonary artery pressure and may even suggest PAH in normal individuals.5

	The use of the 6-minute walk test can be effective in evaluating patients with known PAH. In randomized clinical trials, results of the 6-minute walk have been shown to be an independent predictor of mortality.5 Cardiac cathe-terization (of the right and left sides

	of the heart) is the gold standard for diagnosis and quantification of PAH. It also allows for an assessment of prognosis. PAH cannot be confirmed without cardiac catheterization.

	The diagnosis of PAH does not necessarily preclude an active lifestyle. Patients with advanced PAH and symptoms of dizziness, lightheadedness, or severe dyspnea are at increased risk for life-threatening syncope, however.3

	Women of childbearing age should be counseled against pregnancy. Pregnancy in patients with PAH is associated with an unacceptably high maternal and fetal mortality rate.5 When chronic hypoxemia develops in the setting of PAH, supplemental oxygen therapy is indicated to maintain oxygen saturation above 90%.3

	Diuretic therapy appears to have a marked benefit in patients with PAH. Clinical improvement has been achieved with diuretics in patients with right-sided heart failure.3 The fear that diuretics will induce systemic hypotension is unfounded because the main factor limiting cardiac output is pulmonary vascular resistance, not pulmonary blood volume.5

	Digoxin (Lanoxin) may be most beneficial in the treatment of PAH patients with concomitant intermittent or chronic atrial fibrillation. There are no data from long-term, randomized, double-blind studies to provide clear treatment guidelines regarding the use of digitalis.3

	The rationale for treating PAH patients with anticoagulant therapy is based on the presence of traditional risk factors for venous thromboembolism. These include congestive heart failure, sedentary lifestyle, and thrombophilic disposition. There are no data to specifically support the use of anticoagulation therapy in PAH. The consensus from limited studies is that a target international normalized ratio of 1.5 to 2.5 is recommended.3

	Prostacyclin is the main product of arachadonic acid in the vascular endothelium. It induces the relaxation of the vascular endothelium and vascular smooth muscle by stimulating production of cyclic adenosine monophosphate (c-AMP).3 Epoprostenol sodium (Flolan) has been approved for the treatment of PAH since the 1990s. Continuous pump infusion epoprostenol has been shown in randomized clinical trials to improve quality of life and symptoms related to primary pulmonary hypertension. Benefits included improved results for the 6-minute walk test, decline in mean atrial pressure, decline in mean pulmonary pressure, and increase in cardiac output.5

	Iloprost (Ventavis) is a chemically stable prostacyclin analogue that is available in an aerosol formulation.6 One study showed a reduction of 10% to 20% in mean pulmonary artery pressure after a single inhalation of iloprost, which lasted for 45 to 60 minutes.6 Because of the short half-life of iloprost, however, frequent inhalations are required (up to 12 times per day).5 Overall, inhaled iloprost was well tolerated, with cough, flushing, and headache being the most common side effects.6 At present, iloprost is not available in the United States.5

	In addition to exerting a direct vasoconstrictor effect, endothelin-1 stimulates the proliferation of vascular smooth muscle cells, induces fibrosis, and is a proinflammatory mediator.3 Bosentan (Tracleer) is a nonselective endothelin-receptor blocker that is approved by the Food and Drug Administration (FDA) for the treatment of PAH. In a 12-week, placebo-controlled trial of 32 patients with PAH, bosentan was superior to placebo in increasing the distance walked in the 6-minute walk test (mean gain, 76 m) and in improving hemodynamic measurements.3 Patients receiving bosentan also had improvement in the time to clinical worsening, which included lung transplantation, hospitalization for PAH, and death.3

	The treatment of pulmonary hypertension has been handicapped in the past by limited therapeutic choices. Recently, the FDA has approved sil-denafil, under the trade name Revatio, for the treatment of pulmonary hypertension. In a double-blind study versus placebo involving 277 patients, sildenafil was shown to increase (placebo corrected) the 6-minute walk distances of 45 to 50 m; effects were seen at the 4-week mark. The effects were sustained until the close of the study at 12 weeks. There was also a notable decrease in mean pulmonary artery pressure and systemic vascular resistance.7

	It is becoming increasingly apparent that the combination of pathophysiology of disease and targeted pharmacotherapy are changing the treatment of this disease. The approval of sildenafil represents a continuation of the progress that has been made in treating this debilitating disease state.

Pulmonary arterial hypertension:  A review 

	Diabetic patients have been the major population subset in which high restenosis and event rates have made percutaneous coronary interventions controversial as the preferred revascularization strategy, particularly in those with multivessel disease. Despite the recent ubiquitous use of bare metal stents, diabetic patients clearly have derived less benefit because of more aggressive fibrointimal hyperplasia, resulting in higher angiographic restenosis and revascularization rates. However, the recent arrival of drug-eluting stents (Cypher sirolimus-eluting stent and Taxus paclitaxel-eluting stent) promises to even the playing field between diabetic and nondiabetic patients.

	Drs. Addo and Moussa (page 18) report on the SIRolImUS (SIRIUS)-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions trial substudy demonstrating the benefits of the sirolimus-eluting stent in diabetic patients compared with a bare metal stent. The sirolimus-eluting stent reduced target lesion revascularization from 22.3% to 6.9% (P < .001) and major adverse cardiac events from 25% to 9.2% (P < .001). In comparison, nondiabetic patients had a reduction in target lesion revascularization from 14.1% to 2.99% (P < .001) and in major adverse cardiac events from 16.5% to 6.5% (P < .001).

	The 9-month Diabetes and Sirolimus-Eluting Stent trial,1 which compared sirolimus-eluting stents with bare metal stents in diabetic patients, recently reported similar results. There was an 88% reduction in late lumen loss (P < .001) and a 76% reduction of in-segment restenosis (P < .001) at 9 months with the sirolimus-eluting stent. The rate of major adverse cardiac events was 11.3% with a sirolimus-eluting stent versus 36.3% with a bare metal stent, largely driven by a target lesion restenosis of 31.3% with the bare metal stent versus 7.5% with the sirolimus-eluting stent. There were no differences in cardiac death or myocardial infarction (MI) rates between the groups.

	The meta-analysis2 of TAXUS II, IV, and VI included 458 diabetic patients (154 insulin-dependent). Treatment with the paclitaxel-eluting stent reduced target lesion revascularization at 1 year by 68% in nondiabetic patients (14.2% to 4.6%; P < .001), 71% in non—insulin-dependent diabetics (21.4% to 6.2%; P = .001), and 71% in insulin-dependent diabetic patients (19.3% to 5.6%; P = .015). Both sirolimus and paclitaxel block the phosphatidlyinositol-3-kinase pathway mechanism by which insulin promotes restenosis, which is amplified in insulin resistance. Paclitaxel also blocks the mitogen-activated protein kinase (MAPK) pathway, which promotes restenosis in insulin-dependent diabetic patients. In the recently reported REALITY trial, a comparison of the sirolimus-eluting and paclitaxel-eluting stents demonstrated greater fibrointimal hyperplasia inhibition and less frequent stent thrombosis overall with the sirolimus-eluting stent, although no significant difference was noted in in-lesion restenosis when comparing stents in the diabetic subgroup.3

	Drug-eluting stents have not eliminated the need for adjunctive therapy in the diabetic patient. In particular, suboptimal glycemic control (usually defined as a hemoglobin A1C level above 7.0%), as demonstrated in TAXUS,2 is associated with an increase in restenosis risk after treatment with a drug-eluting stent (3.8% versus 0%). Despite improvements in target vessel revascularization rates with drug-eluting stents, diabetic patients remain at increased risk of MI and death. Periprocedural platelet glycoprotein IIb/IIIa inhibitor therapy has improved survival at 6 months in diabetic patients treated with bare metal stents.4 Pending reports of their efficacy in patients treated with drug-eluting stents, it is reasonable to continue to base their use on periprocedural risk assessment. Diabetes is a prothrombotic state. Diabetic patients, in particular, should be considered for prolonged antiplatelet therapy because of reports showing delayed subacute thrombosis due to delayed reendothelialization in patients treated with drug-eluting stents, as well as demonstrated treatment efficacy.5,6

	The drug-eluting stent trials7 have also demonstrated that nontarget lesion events are particularly significant in affecting long-term prognosis. One-year outcomes after sirolimus-eluting stent treatment demonstrated no difference in target vessel revascularization in nondiabetic patients versus non—insulin-dependent diabetic patients and insulin-dependent diabetic patients (1% versus 2% versus 2.9%), but there was a difference in death (1.5% versus 4% versus 8.8%; P = .08) and acute MI (0% versus 2% versus 5.9%; P = .002). It is important to remember that the stented lesion is a marker, particularly in the diabetic patient, for much more extensive coronary disease. Secondary risk factor modification is, therefore, essential if the long-term mortality rate after stenting is to equal or better that of surgical revascularization.

Preventing restenosis in diabetic patients with drug-eluting stents

	On June 8, 2004, a 62-year-old Caucasian man was referred to our cardiac catheterization laboratory for diagnosis and treatment of suspected ischemic heart disease. He had had diabetes for 5 years, and mild hypertension. Over the previous 4 months he had experienced intermittent brief episodes of chest discomfort and shortness of breath, commonly when he was under mental stress or during abrupt physical activity. His medications included lisinopril (Prinivil, Zestril), 10 mg daily, metformin (Glucophage, Riomet), 1,000 mg twice daily, aspirin, 81 mg daily, and simvastatin (Zocor), 10 mg daily. On physical examination he appeared slightly obese but was otherwise well. His cardiovascular examination was normal, his blood pressure was 132/65 mm Hg, and his pulse was 70 beats per minute. Standard laboratory studies including blood counts and renal function were within normal limits. The measured total cholesterol was 199 mg/dL, triglycerides 205 mg/dL, and high-density lipoprotein cholesterol 38 mg/dL. Calculated low-density lipoprotein cholesterol was 127 mg/dL and glycosylated hemoglobin A1C was 6.8%.

	An exercise stress test with perfusion imaging had been performed 8 days before the visit. He exercised for 7 minutes and 20 seconds on a standard Bruce Protocol, stopping for fatigue and vague neck discomfort, achieving a peak heart rate of 140 beats per minute. The electrocardiogram at baseline was normal but at peak stress showed 1 mm

	diffuse flat ST-segment depression. Perfusion imaging showed a large area of ischemia of moderate intensity involving the anterolateral left ventricle. Left ventricular function was normal and the calculated ejection fraction

	Diagnostic coronary angiography was performed in standard fashion and revealed a high-grade stenosis, 85% to 90% diameter obstruction in the proximal left anterior descending (LAD) coronary artery. The lesion measured 16 mm in length, was mildly calcified, and spanned a small septal perforator branch. The reference vessel size distal to the lesion was 3.3 mm in diameter, while the proximal reference measured 3.6 mm. In the left circumflex system there was a moderately severe discrete lesion, 60% to 75% diameter stenosis in the mid-portion of the first obtuse marginal branch. This vessel had reference measurements of 3.0 and 3.2 mm. The rest of the coronary arteries showed diffuse luminal irregularities consistent with mild-to-moderate atherosclerosis. Left ventriculography was normal, with an estimated ejection fraction of 55%.

	Percutaneous coronary intervention was carried out in standard fashion. A 3.5 x 23 mm sirolimus-eluting stent (Cypher) was placed in the LAD and a 3.0 x 13 mm sirolimus-eluting stent was placed in the first obtuse marginal branch with excellent angiographic results. The procedure was uncomplicated and a creatine kinase MB fraction the next morning was normal. The patient was discharged with instructions to continue clopidogrel (Plavix) for 12 months and to double the dose of simvastatin as tolerated.

	Until recently, coronary artery bypass graft (CABG) surgery would have been the superior treatment in this patient with diabetes with double-vessel coronary artery disease of this type. Today, based on recently published data,1,2 we expect his risk of death or myocardial infarction over the next 3 years to be no different compared with CABG. Furthermore, his risk of restenosis is less than 10% for each lesion.3,4

Which intervention is best for  a diabetic patient with suspected ischemic heart disease?

	Several studies have linked the increasing incidence of diabetes to an increased prevalence of cardiovascular disease.1,2 Diabetes is known to accelerate coronary atherosclerosis and to worsen the short- and long-term prognosis of patients with cardiovascular disease.3-6 Furthermore, compared with nondiabetic patients, outcomes are worse when patients with diabetes undergo coronary revascularization either by coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI).7-9 A significant contributor to worse outcomes after PCI in diabetic patients is restenosis, which remains as high as 25% to 50% with standard coronary stents.10,11 The introduction of drug-eluting stents represents a significant leap forward owing to its efficacy in reducing restenosis in the overall population.12-15 However, it is important to assess whether these results can be generalized to patients with diabetes. The purpose of this review is to summarize the results of the diabetes subanalysis of the SIRolImUS (SIRIUS)-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions trial that was recently published.16

	The SIRIUS trial was a prospective, randomized, double-blind study of 1,058 patients that was conducted to evaluate the efficacy of sirolimus-eluting stents in a well-defined patient cohort.13 In the diabetes subanalysis of this trial, we compared the outcome of patients with diabetes mellitus (279 patients) to those without diabetes (778 patients) based on their treatment assignment (sirolimus-eluting stent [Cypher] versus bare metal stent). Clinical follow-up was obtained at 30 days, 6 months, and 9 months. Coronary angiograms obtained at study entry and at the 8-month follow-up were analyzed independently at a dedicated core laboratory. All statistics were performed using the SAS system (version 6.12), and reported P values were two-sided.  

	Patients with diabetes were more commonly women (39% versus 25%, P < .001) and had a higher prevalence of hypertension (79.5% versus 63.5%, P < .001) and triple-vessel disease (19.7% versus 12.7%, P = .006). Vessel diameter was smaller in diabetic patients (2.75 ± 0.44 mm versus 2.82 ± 0.47 mm, P = .03), but there were no differences in the other baseline angiographic characteristics.

	Angiographic follow-up was completed in 67% and 66% of diabetic and nondiabetic patients, respectively. Sirolimus-eluting stents reduced in-lesion restenosis in patients with diabetes from 50.5% to 17.6% (P < .001) and in nondiabetic patients from 30.7% to 6% (P < .001). Furthermore, in-stent restenosis was transformed from a diffuse pattern with bare metal stents to a focal pattern with sirolimus-eluting stents in both diabetic and nondiabetic patients (Table). At 9 months’ follow-up, the primary end point of target vessel failure was significantly reduced from 27% to 12.2% (P = .003) in diabetic patients, and from 18.6% to 7.7% (P < .001) in the nondiabetic patients. An intriguing finding of this study was that the reduction of in-lesion restenosis in insulin-requiring patients (50% to 35%, P = .38) was not as significant as that in non—

	insulin-requiring patients (49.3% versus 7.7%, P < .001) owing to an unexpectedly high frequency of stent edge restenosis in insulin-requiring patients.

	The diabetic subanalysis of the SIRIUS trial demonstrated that not only are sirolimus-eluting stents safe in patients with diabetes, but they are also effective in reducing angiographic and clinical recurrence to a level similar to that in nondiabetic subjects. In addition, even when restenosis occurs, it is often focal and therefore more amenable to repeat percutaneous treatment. It is also reassuring that the attenuated efficacy of sirolimus-eluting stents in insulin-requiring patients seen in this trial was not observed in more recent trials.14,17

	In conclusion, the use of sirolimus-eluting stents in patients with diabetes is highly effective in reducing restenosis and improving clinical outcomes.

Are drug-eluting stents as  useful in patients with diabetes  as in nondiabetic patients?

	San Diego—The first drug to reach phase 3 trials in a promising new class of agents called the dual alpha/

	gamma peroxisome proliferator-activated receptor (PPAR) agonists is superior to pioglitazone in improving lipid parameters and achieving long-term glycemic control, said David Kendall, MD, at the 65th Annual Scientific Sessions of the American Diabetes Association.

	The agent, muraglitazar, targets the PPARs. The thiazolidinediones target PPAR-gamma, thereby improving insulin sensitivity and glycemic control. In addition to PPAR-gamma, muraglitazar has activity at PPAR-alpha, which is associated with regulation of lipids.

	A second dual PPAR agonist, tesaglitazar, reduced fasting plasma glucose and improved lipid parameters in comparison with placebo in a phase 2 study.

	“These new compounds address three of the most critical areas in diabetes: glucose control, triglycerides, and high-density lipoprotein [HDL],” said Dr. Kendall, associate professor of medicine, University of Minnesota Medical School.

	2 diabetes who had not reached adequate glycemic control goals despite treatment with 1,500 mg/day or more of metformin, patients were randomly assigned to receive either 5 mg of muraglitazar or 30 mg of pioglitazone daily for

	24 weeks while metformin doses were maintained at baseline levels. HMG-CoA reductase inhibitor (statin) therapy was permitted, as needed, after the first 12 weeks of the study.

	After 24 weeks, patients assigned to muraglitazar had a mean reduction in glycosylated hemoglobin (A1C) of 1.14% compared with a mean reduction of 0.85% in the pioglitazone recipients (P < .001). Sixty percent of the muraglitazar group versus 45% of pioglitazone patients achieved goal A1C levels of less than 7% (P < .001).

	Fasting plasma glucose levels were reduced by 44 mg/dL from baseline in the muraglitazar group and 33 mg/dL in the pioglitazone group (P < .001). Muraglitazar also produced significantly greater reductions in fasting plasma insulin than did pioglitazone (5.0 mU/mL versus 3.6 mU/mL;

	Muraglitazar was also associated with a 30% reduction in C-reactive protein levels compared with a 24% reduction in pioglitazone-treated patients (P = .04) and a 30% reduction in plasminogen-activator inhibitor-1 levels compared with a 22% decrease with pioglitazone (P = .002).

	Muraglitazar-treated patients had significant improvements in lipid values at 12 weeks (before statin initiation). Patients assigned to muraglitazar experienced a 28% reduction in triglyceride levels from baseline compared with a 14% reduction for pioglitazone-treated patients (P = .001). Among those who had triglyceride levels greater than 150 mg/dL at baseline, muraglitazar was associated with a 35% reduction versus a 19% reduction for pioglitazone (P < .001).

	HDL cholesterol values increased 19% in the muraglitazar group at 12 weeks, compared with 14% in the pioglitazone group (P = .001). Non-HDL cholesterol levels decreased by 6%, apolipoprotein B levels decreased by 12%, and free fatty acid levels decreased by 30% with muraglitazar, compared with decreases of 1%, 6%, and 21%, respectively, for pioglitazone (P < .001 for all values).

	Preliminary analysis of a 26-week continuation of the study shows that the glycemic control and lipid differences between the two treatment groups were maintained or increased after 50 weeks of total treatment time.

	In an extension of a previous dose-ranging, phase 2 trial, patients taking 5 mg of muraglitazar maintained A1C levels that were 1.52% below baseline after 104 weeks’ treatment. “This 2-year durability study shows that the 5-mg dose has remarkable stability of glucose control,” Dr. Kendall said.

	azar than pioglitazone (mean: 1.4 kg versus 0.6 kg). “The initiation of metformin treatment with muraglitazar may limit weight gain,” Dr. Kendall said.

	Four muraglitazar-treated patients developed adverse events related to heart failure compared with one patient in the pio-

	glitazone group, all of which resolved with diuretic therapy and/or withdrawal of the study drug. Hypoglycemia occurred in three patients in the muraglitazar group and one in the pioglitazone group, but no hypoglycemia-related serious events or study withdrawals occurred due to hypoglycemia.

	Tesaglitazar was studied in a 12-week, randomized, double-blind, placebo-controlled, phase 2, dose-ranging (0.1 to 3.0 mg) study of 500 patients with type 2 diabetes. Compared with placebo, fasting plasma glucose was reduced in a dose-dependent fashion by up to 61 mg/dL

	(P < .001), fasting triglycerides were reduced by up to 41% in a dose-dependent manner (P < .001), HDL cholesterol increased by 15% (P < .001) with a plateau reached at 1.0 mg of tesaglitazar, and low-density lipoprotein cholesterol was reduced in a dose-dependent manner by up to 17% (P < .001).

	“The past focus in type 2 diabetes management has been glucose; however, there is an increasing need for a single agent that can target both glucose and dyslipidemia associated with type 2 diabetes,” said lead investigator Barry J. Goldstein, MD, PhD, director of the division of endocrinology, diabetes and met-abolic diseases at Jefferson Medical College, Philadelphia.

 Dual PPAR agonists improve glycemic control, lipids in type 2 diabetes

	San Diego—New treatments for type 2 diabetes are focusing on increasing circulating levels of glucagon-like peptide-1 (GLP-1), a crucial incretin hormone released from the intestinal tract that stimulates beta cells to produce insulin.

	GLP-1, the incretin mimetics, was the subject of several presentations at the 65th Annual Scientific Sessions of the American Diabetes Association. The first of the incretin mimetics to be approved by the FDA is exenatide (Byetta), which produced sustained improvements in glucose control and weight, in addition to clinically meaningful improvements in cardiovascular risk factors.

	GLP-1 inhibits glucagon secretion, regulates gastric function, and may promote satiety—effects that reduce glycemic excursions after food intake, said David D’Alessio, MD. These effects are less pronounced in patients with diabetes.

	Persons with type 2 diabetes produce high levels of glucagon, signaling the liver to produce glucose. Pharmacologic administration of GLP-1 has been shown to improve glycemia in patients with diabetes through suppression of glucagon secretion and gastric emptying, as well as by stimulating the beta cell, said Dr. D’Alessio, associate professor of medicine, University of Cincinnati.

	“The main effect of GLP-1 treatment is to modify islet function,” said Bo Ahrén, MD. “Defective islet function is a key defect for not only the cause of the disease but also for the progressive deterioration of the disease. If we can affect the islet function in a beneficial way, we have for the first time a treatment modality that can potentially modify the disease process.”

	GLP-1—based therapy may fulfill several unmet needs in the treatment of type 2 diabetes, said Dr. Ahrén, professor of medicine, and head, research department, Lund University Hospital, Malmö, Sweden. No other treatments that are available inhibit glucagon secretion or increase beta cell mass, he said.

	GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV), making it unattractive as a treatment. Two strategies have evolved to overcome this drawback, however, the first being injectable GLP-1 receptor agonists such as exenatide. The second strategy is to inhibit DPP-IV and thereby take advantage of the increase of GLP-1 after each meal, increasing the endogenous concentration of GLP-1. The DPP-IV inhibitor farthest along in clinical trials is vildagliptin, which can be given orally.

	In open-label extension studies of 265 patients treated for an average of more than 82 weeks, exenatide in combination with metformin, a sulfonylurea, or both, resulted in an average reduction in glycosylated hemoglobin (A1C) levels of 1.2% and an average body weight reduction of 10.1 lb, said David Kendall, MD, chief of clinical services and medical director at the International Diabetes Center in Minneapolis.

	Furthermore, favorable changes in triglycerides, high-density lipoprotein (HDL) cholesterol, and blood pressure were observed with exenatide. From baseline to 82 weeks, triglycerides decreased by a mean of 36.94 mg/dL, HDL cholesterol increased by a mean of 4.46 mg/dL, and blood pressure declined by a mean of 1.48/3.24 mm Hg. “Improvements in cardiovascular risk factors were greatest in patients who experienced the greatest reductions in weight,” said Dr. Kendall.

	Vildagliptin is an oral DPP-IV inhibitor that has been shown to improve glucose tolerance, maintain the insulin response, and decrease glucagon response in type 2 diabetes, said Steven E. Kahn, MB, professor of medicine, University of Washington, Seattle. Vildagliptin acts in synergy with metformin to improve glucose control and beta cell function.

	When given with metformin for 1 year, vildagliptin improved beta cell func-

	tion and increased sensitivity to insulin after eating a meal compared with patients taking metformin alone, reported Dr. Ahrén. In animal models, vildaglip-

	tin treatment decreased the rate of beta cell death and increased beta cell replication, leading to a 40% to 50% increase in the number of insulin-producing beta cells. Phase 3 studies of vildagliptin are continuing.

 GLP-1%u2013based therapy improves cardiovascular risk factors

	San Diego—Delaying the onset of type 2 diabetes has a substantial impact on predicted vascular events, found researchers from the Cardiff Research Consortium, United Kingdom, who presented their data at the American Diabetes Association’s 65th Annual Scientific Sessions.

	Led by Phil McEwan, PhD, director and senior research mathematician, they predicted the incidence of microvascular and macrovascular events and costs associated with type 2 diabetes by following a cohort of 1,000 newly diagnosed diabetes patients over a 20-year horizon.

	Depending on the risk equation used in the analysis, up to 16 coronary heart disease events could be avoided by delaying diabetes by 2 years, up to 68 could be avoided by delaying it for 5 years, and up to 122 could be avoided by delaying it for 10 years. The maximum number of stroke events avoided was 37, 92, and 143 for

	2-, 5-, and 10-year delays, respectively. The number of cardiovascular deaths avoided was as high as 22, 70, and 129 for delays of 2, 5, and 10 years, respectively.

	The maximum number of retinopathy, nephropathy, and neuropathy events avoided following a 10-year delay in the onset of diabetes was 453, 325, and 107, respectively.

	Cost savings were also associated with delaying diabetes, they found. “Increased awareness of the benefit of delaying or preventing the onset of diabetes is essential, and substantial clinical and economic benefit can be obtained,” said Dr. McEwan.

	In other data presented here, a blood glucose level of 100 to 125 mg/dL, known as “prediabetes,” is associated with an increased risk of cardiovascular complications and significantly elevated health care costs, said Gregory A. Nichols, PhD.

	According to Dr. Nichols, senior research associate at Kaiser Permanente Center for Health Research, Portland, Ore, annual health care costs for persons with blood glucose levels toward the upper range of prediabetes were 31% greater than the costs for persons with normal blood glucose levels, “with many of the extra costs due to cardiovascular disease, which is expensive to treat but far less expensive to prevent.”

	In a 9-year study, 28,335 Kaiser Permanente participants with elevated levels of blood glucose but without diabetes were stratified into two groups: those with blood glucose values of 100 to 109 mg/dL (stage 1 prediabetes) and those with blood glucose values of 110 to 125 mg/dL (stage 2 prediabetes). Most of the patients remained in their original stage, but 3,281 progressed.

	The subjects were followed until they advanced to the next stage of blood glucose level; received an oral antidiabetic drug, indicating a diagnosis of diabetes; terminated their health plan participation; or reached the end of the 9-year study period.

	Annual costs adjusted for age and sex were $4,357 for patients with normal glucose levels, $4,580 for those with stage 1 prediabetes, and $4,960 among those with stage 2 prediabetes. When excluding those subjects who progressed to stage 2 prediabetes or diabetes, the annual costs for subjects with normal blood glucose were only $3,799. The increased costs with elevated fasting plasma glucose were observed for inpatient, outpatient, and pharmacy expenses.

	Examination of diagnostic codes revealed a greater prevalence of cardiovascular disease and obesity in those with elevated fasting glucose levels, to which the authors attributed the higher medical costs.

 Delaying diabetes can also delay vascular events

	San Diego—In phase 3 clinical trials in patients with type 2 diabetes, the endocannabinoid antagonist rimonabant (Acomplia) lowered blood glucose levels, reduced weight and waist circumference, and improved the lipid profiles associated with diabetic dyslipidemia, according to data presented at the 65th Annual Scientific Sessions of the American Diabetes Association.

	One-year data from a phase 3 study of 1,045 patients with type 2 diabetes who were receiving treatment with oral antidiabetic medications were presented by André Scheen, MD, head of clinical pharmacology, division of diabetes, nutrition, and metabolic disorders, Academic Hospital of Liège, Belgium, and principal investigator of the study, known as Rimonabant in Obesity (RIO)-Diabetes.

	“The RIO-Diabetes trial results indicated that rimonabant delivered a clinically meaningful reduction in glycosylated hemoglobin [A1C] and may offer a broad range of cardiometabolic risk factor improvements that are essential for the comprehensive management of people with type 2 diabetes,” said Dr. Scheen.

	RIO-Diabetes was a multicenter, randomized, double-blind trial in which two fixed-dose regimens of rimonabant (5 mg and 20 mg once daily) were compared with placebo for 1 year in patients with type 2 diabetes who had a mean waist circumference of 43.3 in. The patients were already being treated with either metformin or a sulfonylurea when they entered the study.

	Compared with placebo, patients assigned to 20 mg/day of rimonabant achieved an A1C reduction of 0.7% (P < .001), from a baseline value of 7.3%. Forty-three percent of patients randomly assigned to rimonabant, 20 mg/day, and 21% of those assigned to placebo (P < .001) achieved an A1C less than 6.5%, a target set by the International Diabetes Federation and the American Association of Clinical Endocrinologists. Among those with a baseline A1C higher than 7.0%, which is the treatment goal set by the American Diabetes Association, 52.7% assigned to rimonabant, 20 mg/day, and 26.8% assigned to placebo (P < .001) reduced their A1C to below this goal by study’s end.

	There was a mean weight reduction of 5.3 kg in patients treated with 20 mg/day of rimonabant versus 1.4 kg in the placebo recipients (P < .001). There was an average 1.3-in difference in waist circumference between the groups receiving rimonabant, 20 mg/day, and placebo.

	High-density lipoprotein (HDL) cholesterol increased by 15.4% in patients treated with rimonabant, 20 mg/day, compared with 7.1% in the placebo group (P < .001). More than 50% of the improvement in HDL cholesterol levels was calculated to be beyond the improvement attributed to the weight loss achieved, said Dr. Scheen. Triglyceride levels were reduced by 9.1% in those assigned to rimonabant, 20 mg/day, whereas triglycerides increased by 7.3% in the placebo group (P < .001).

	The proportion of patients meeting the criteria for a diagnosis of metabolic syndrome decreased by 18.9% of patients assigned to rimonabant, 20 mg/day, compared with a decline of 7.6% in the placebo group (P = .007).

	Adverse effects of the 20 mg/day rimonabant treatment included nausea (12.5% versus 5.7% for placebo), dizziness (9.1% with rimonabant versus 4.9% with placebo), diarrhea (7.4% with rimonabant versus 6.6% with placebo), vomiting (5.9% with rimonabant versus 2.3% with placebo), hypoglycemia (5.3% with rimonabant versus 1.7% with placebo), fatigue (5.3% with rimonabant versus 3.7% with placebo), and anxiety (5.0% with rimonabant versus 2.6% with placebo). The rates of discon-

	tinuation owing to adverse events across the entire phase 3 program of rimonabant were 13.8% in the group assigned to rim-onabant and 7.2% in the group assigned

Phase 3 study shows improvements in A1C and cardiometabolic risk factors in patients with type 2 diabetes

	San Diego—Intensive blood glucose control for 6 years followed by less intensive control for the next decade reduces the long-term risk of cardiovascular events in patients with type 1 diabetes, said David M. Nathan, MD, at the 65th Annual Scientific Sessions of the American Diabetes Association.

	In the Diabetes Complications and Control Trial (DCCT), 1,441 patients aged 13 to 39 years with type 1 diabetes were randomly assigned to intensive management of blood glucose or conventional control. The randomized portion of the trial lasted from 1983 to 1989. Those randomly assigned to intensive control used three or more daily insulin injections or an insulin pump guided by frequent self-monitoring of blood glucose levels to achieve average glycosylated hemoglobin (A1C) levels as close as possible to 6% or less. Conventional treatment consisted of one or two insulin injections per day with daily urine or blood glucose testing.

	in mean A1C levels between the two groups, which resulted in a significant reduction in the incidence of retinopathy, neuropathy, and nephropathy in the intensively treated group.

	During the 6-year study period, the incidence of cardiovascular events in the intensively treated group was lower than that in the control group (3 versus 14, respectively), but the total number of events was too low to draw any meaningful conclusions, said Dr. Nathan, director of the General Clinical Research Center and the diabetes center at Massachusetts General Hospital, and professor of medicine at Harvard Medical School, Boston.

	A1C levels in the two groups drifted together after the original 6 years, to about 8%. Despite this leveling off of A1C levels, the benefits of the original 6 years of intensive control have persisted.

	The long-lasting value of intensive control was evident in the difference in the number of cardiovascular events between the two groups over follow-up a decade after the original results were announced. The intensively treated patients had 57% fewer such events compared with the conventionally treated group (46 versus 98, respectively). Thirty-one intensively treated patients and 52 conventionally treated ones had at least one cardiovascular event during the 17 years of follow-up.

	The rate of cardiovascular events per 100 patient-years was 0.38 in the intensively treated group and 0.80 in the control group (P = .007). The cumulative rate of cardiovascular events was 6% in the intensively treated group and 11% in the controls, for a 42% reduction (P = .016).

	A history of microalbuminuria conferred a 2.9-fold increased risk of cardiovascular events and a history of albuminuria conferred a 2.2-fold increased risk. Adjusting for the difference in microalbuminuria and albuminuria between the two treatment groups explained only a small portion of the treatment effect. “The difference in A1C during DCCT explained 97% of the treatment effect,” said Dr. Nathan. The reduction in cardiovascular events in the intensively treated group “is mediated by changes in glycemia and cannot be entirely explained by kidney disease,” he said.

	In another study presented here, Saul Genuth, MD, of Case Western University, Cleveland, said glycation products could explain the “metabolic memory” phenomenon in DCCT. Based on a comparison of skin biopsies in 215 people in each treatment group, researchers found that those who had the highest level of glycation products 10 years ago have had more severe progression of complications, particularly retinopathy and nephropathy, which is strong evidence that those products may be associated with diabetic complications.

Tight glucose control produces long-lasting cardiovascular  benefits in type 1 diabetes

	Cardiology Review (CR) recently spoke with Anne L. Taylor, MD, professor and associate dean at the University of Minnesota School of Medicine and lead investigator of the African-American Heart Failure Trial (A-HeFT).1

	CR: The A-HeFT trial showed a 43% improvement in survival for heart failure patients, but it was also the first clinical trial conducted in an all African American population. What do you believe will be the impact of this trial on future clinical trials involving African Americans?

	Dr. Taylor: I think this is going to tell us how critically important it is to have diversity in clinical trials—to have both women and minorities included in sufficient numbers so that we can do subgroup analyses to show whether responses are the same or different. There will not always be population differences by ethnicity; differences may be by gender, by environmental factors, or by lifestyle factors, but we need to look at populations so that we can understand what’s different and what’s the same.

	The FDA makes their labeling decisions about products based on data from controlled clinical trials, and the A-HeFT data were strong. The trial certainly dem-onstrated a huge benefit in African Americans, so I think the big question is whether there will be other groups that will benefit from this fixed-dose combination (isosorbide dinitrate and hydralazine). We also have to figure out the mechanism by which the drug works, and how we would identify responsiveness in other groups. We have data from the Vasodilator-Heart Failure Trial (V-HeFT)2 that really showed a difference in the response between African Americans and white subjects (with isosorbide dinitrate/hydralazine versus prazosin) and that was one of the reasons for conducting this trial in the African American population. V-HeFT was based on very small numbers, and it was done 25 years ago, so those patients were not on contemporary medications. So it was extremely important to do this trial to confirm that suggestion of a benefit and we did confirm it. I think that ultimately we will find other populations that will benefit from this combination, which has been used for many years in heart failure patients. The Heart Failure Society Guidelines, for example, recommend the use of this combination for patients who have kidney disease. What I think it will do now is shift the recommendations to say that this is especially effective in African Americans but it may be effective in other subsets of patients.

August 2005

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Tight glucose control produces long-lasting cardiovascular benefits in type 1 diabetes

Anne Taylor, MD, comments on A-HeFT

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