• Baseline data from an ongoing major clinical trial points out that elderly heart failure patients who have an acute myocardial infarction (MI), are at greater risk of early death or stroke, because they are less frequently treated with aspirin, beta blockers, or reperfusion therapy.
• A novel direct thrombin inhibitor significantly reduces adverse ischemic and hemorrhagic events in patients with a variety of manifestations of coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI).
• Antiplatelet inhibition has been shown to be of considerable benefit in patients with acute coronary syndrome (ACS) undergoing PCI, with or without stents.
• Switch therapy to a more effective statin when other statins fail to reach the target LDL-cholesterol goals brings significantly more persons within target goal levels safely and effectively.
• A new dual combination lipid-lowering formulation is a safe and well tolerated method for treating patients with dyslipidemia.
• The addition of a unique cholesterol absorption inhibitor to one of the standard statins results in a significantly greater reduction in the level of LDL-cholesterol than doubling the dose of the statin alone in patients with hypercholesterolemia.
• Early statin therapy following PCI significantly reduces the risk of major adverse cardiovascular events (MACE), whether or not stenting was carried out in the initial PCI procedure.
• A meta-analysis of three major clinical trials points out that a low molecular weight heparin (LMWH) is significantly more effective than unfractionated heparin in reducing ischemic complications and fewer deaths in patients with an acute MI treated with fibrinolysis.
• Results from what is being stated as a landmark clinical trial have demonstrated that a new, orally administered anticoagulant is more effective, safer, easier to administer, and causes less bleeding than well-controlled warfarin for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF).
• Beta blockade with a long-acting, controlled-release beta blocker is markedly more effective than standard antiarrhythmics for maintaining patients with AF in sinus rhythm, offering these individuals better long-term outcomes.
• A recombinant form of human B-type natriuretic peptide is being recommended as a cost-effective approach for the treatment of decompensated congestive heart failure (CHF) in an emergency department setting.
• While ACE inhibition and beta blockage are still the initial treatment of choice in mild CHF, beta blockade alone has been shown to produce a significant reversal of cardiac remodeling compared to ACE inhibition alone.
• This article which highlights results from a number of major clinical trials and subgroup analyses of earlier clinical trials for the treatment and prevention of CAD, ACS, hypercholesterolemia, AF, and CHF, was written by Lawrence M. Prescott, Ph.D.

Introduction
The latest findings from key clinical studies and landmark clinical trials were presented at the American College of Cardiology's 52nd Annual Scientific Session. These presentations represent a wide variety of pharmacologic approaches, many of which are presently or will soon be considered standards of care in the prevention, treatment and control of cardiovascular disease.

Treating the Elderly with Heart Failure After an Acute MI
Baseline data from the VALIANT (VALsartan In Acute myocardial INfarction Trial) study show that elderly patients with heart failure and/or left ventricular systolic dysfunction (LVSD) who have an acute myocardial infarction (MI) are not likely to receive aggressive treatment, leading to increased risks of early death or stroke.

The VALIANT trial is an ongoing prospective randomized trial in which 14,808 patients with heart failure and/or LVSD who have undergone an acute MI are randomized to either the angiotensin converting enzyme (ACE) inhibitor captopril (Captopril®, Mylan), the angiotensin II receptor blocker (ARS) valsartan (Diovan®, Novartis), or both to determine what treatment strategy is best for these MI survivors. Since most trials of patients with heart failure following MI have not enrolled a representative population, with many elderly patients being excluded, and, since the VALIANT trial is the largest survival study with an ARB ever conducted in people who have experienced an MI, this was an excellent opportunity to assess treatment approaches in this important and increasing cohort.

A total of 3,189 patients (21.5%) of the total study population of the VALIANT trial were over 75 years of age. The effects of demographics and outcomes were assessed at 30 days after enrollment in the study in patients over 75 years of age and those under 75 years of age.

Compared with younger patients, elderly patients were more likely to have high-risk demographics, with significantly more elderly being in Killip class III or IV (30.6%) than younger patients (22.1%), more renal insufficiency seen (7.0% vs 3.6%), more elderly with hypertension (61.6% vs 53.3%() and more elderly having a prior MI (33.1% vs 26.5%).

Interestingly, although the older patients generally were in poorer health, they were less frequently treated with aspirin, beta blockers or reperfusion therapy. On multivariate analysis, including all baseline variables, age was an independent predictor of 30-day mortality, with each 10-year increase in age being associated with a 50% increase in 30-day mortality. The overall mortality rate in patients over 75 years of age was 7.2% compared to 3.2% in those under 75 years of age. (White, Harvey D etal. Abstracts of the 52nd Annual Scientific Session of the ACC. Vol 41#6 (Suppl A). Pg 179A:1112-85)

Coronary Artery Disease
Bivalirudin (Angiomax®, The Medicines Company)
In a single center series of patients undergoing percutaneous coronary intervention with the direct thrombin inhibitor bivalirudin, there was a significant reduction of adverse ischemic and hemorrhagic events and glycoprotein IIb/IIIa inhibitor usage compared to present standard of care.

To reach this conclusion, 307 patients undergoing PCI for indications of stable angina, unstable angina, myocardial infarction (MI), positive stress test results or other manifestations of coronary artery disease (CAD) were given bivalirudin as a 0.75 mg/kg bolus and a 1.75 mg/kg/hour infusion during the procedure. Pretreatment with clopidogrel was encouraged. The PCI procedure could include stent implantation, balloon and cutting balloon angioplasty, rotablator, and brachytherapy. Two post-PCI CK-MB measurements were analyzed in all patients except those with acute MI. Stents were implanted in 81% of lesions and 10% of the interventions were in saphenous vein grafts.

The substitution of bivalirudin for heparin resulted in a low rate of adverse events and low glycoprotein (GP) IIa/IIIb inhibitor usage. Hemorrhagic complications were significantly decreased compared to that reported for heparin alone or heparin with a GP IIb/IIIa inhibitor in previously published trials. There were no TIMI major hemorrhages, only 2 minor hemorrhages, no blood transfusions required, no retroperitoneal bleeding, only one death and one Q-wave MI, and GP IIb/IIIa inhibitor usage was required in only 31 patients.

These findings have been confirmed in the REPLACE-2 (The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2) trial (JAMA, February 19, 2003. Vol 289, No 7 Page 853-863). This major clinical study which encompassed 6,010 patients undergoing urgent or elective PCI demonstrated a decrease in acute ischemic endpoints and hemorrhagic events with the use of bivalirudin and provisional GP IIb/IIIa inhibition compared to heparin and routine GP IIb/IIIa inhibition. (Attubato, Michael J etal. Abstracts of the 52nd Annual Scientific Session of the ACC. Vol. 41 #6 (Suppl A). Pg 5A:1005A-219).

Acute Coronary Syndrome
Clopidogrel (Plavix®, Bristol-Myers Squibb/Sanofi Synthelabo)
Analysis of results from the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial has shown that, in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), antiplatelet inhibition with clopidogrel is of considerable benefit both in those treated with a stent and in those undergoing balloon angioplasty alone.

Because, it is not always possible to insert a stent in patients undergoing PCI, an analysis was carried out to examine the consistency of benefit with clopidogrel in those patients treated with or without a stent. Overall, 2,658 patients who underwent PCI in the CURE study were divided in two groups; those receiving a stent and those not receiving a stent. Initially, these patients had been randomly assigned to clopidogrel as a 300 mg loading dose, followed by 75 mg daily for up to one year or matching placebo, both in addition to aspirin.

Among the patients undergoing PCI in the CURE study, there was a significant reduction of 31% in cardiovascular death or myocardial infarction (MI) with clopidogrel compared to placebo. There were 486 evaluable patients who did not receive an intracoronary stent, 253 of whom were in the placebo group and 233 of whom were given clopidogrel. In addition, 2,066 evaluable patients received at least one stent, 1,092 on placebo and 1,080 on clopidogrel. Clopidogrel was beneficial both in those not receiving a stent and in those receiving a stent, with relative risk reductions of 44% and 27% respectively. (Mehta, Shamir R. etal. Abstracts of the 52nd Annual Scientific Session of the ACC. Vol. 41 #6 (suppl A). Pg 45A: 823-6).

Hypercholesterolemia
Rosuvastatin (Crestor®, AstraZeneca)
Switching from a statin that has failed to enable patients to reach their LDL-cholesterol goals to rosuvastatin 10 or 20 mg is an effective strategy for improving LDL-cholesterol goal achievement in hypercholesterolemic patients with or at high risk of coronary heart disease, bringing significantly more persons within international LDL-cholesterol treatment guidelines.

After a six-week dietary lead-in period, 3,161 adults with hypercholesterolemia were enrolled into the MERCURY 1 (Measuring Effective Reductions in Cholesterol Using Rosuvastatin Theory), a 16-week, randomized, 2-period, open label trial, and randomized to open-label rosuvastatin 10 mg, atorvastatin 10 mg, atorvastatin 20 mg, simvastatin 20 mg, or pravastatin 40 mg. One-half of each group except atorvastatin 20 mg switched to rosuvastatin 10 mg at eight weeks, while one-third of patients on atorvastatin 20 mg switched to rosuvastatin 10 mg or 20 mg at eight weeks. To simulate the actual prescribing practice of physicians, the patients who were switched from one treatment to another after 8 weeks did not undergo a treatment washout period. Treatment comparisons were made at 8 and 16 weeks, using logistic regression analyses for percentages of patients achieving European and Adult Treatment Panel III (ATP III) LDL-cholesterol goals and analysis of variance for percentage change from baseline in lipid measures.

Results favoring rosuvastatin over the other statins were seen at weeks 8 and 16. At the end of week 8, rosuvastatin 10 mg brought statistically more patients to the joint European LDL-C goal vs atorvastatin 10 mg, simvastatin 20 mg and pravastatin 40 mg (88%, 76%, 69%, 62% respectively). At 16 weeks, the joint European LDL-C goal was achieved in statistically significant more patients switching to rosuvastatin 10 mg versus those remaining on atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 40 mg and in significantly more patients switching to rosuvastatin versus those remaining on atorvastatin 20 mg.

With regard to lipid changes at 8 weeks, rosuvastatin 20 mg reduced LDL-C by 47%, significantly more than the 37.2% with atorvastatin 20 mg, the 43% with atorvastatin 20 mg, the 35.4% with simvastatin 20 mg, and the 31% with pravastatin 10 mg. In addition, HDL-C was increased by 9.2% with rosuvastatin 20 mg, significantly higher than the 5.7% with atorvastatin 20 mg, 8.0% with simvastatin 20 mg, or 7.6% with pravastatin 40 mg. Comparable reductions in LDL-C and increases in HDL-C were seen at 16 months in the switch rosuvastatin 10 mg and 20 mg groups compared to patients who remained on atorvastatin, pravastatin, or simvastatin. (Schuster, Herbert etal. Abstracts of the 52nd Annual Scientific Session of the ACC. Vol. 41 #6. (suppl A). Pg 227:1010-1401)

Extended-Release Niacin/Lovastatin (Advicor™, Kos Pharmaceuticals)
A novel combination formulation consisting of extended-release niacin and lovastatin (ERNL) has been shown to be safe and well tolerated when given as initial therapy in the treatment of dyslipidemia.

These conclusions were reached from the results of the IMPACT (Impact of Medical Subspecialty on PAcompliance to Treatment) study, an open-label, multi-center, 12-week study. The safety of once-daily ERNL as initial therapy was evaluated in an intent-to-treat population of 4,499 men and women with dyslipidemia. Treatment began with one ERNL 500 mg/ 20 mg tablet once daily at bedtime and, after the first month, the dose was increased to ERNL 1000 mg/40 mg, which was continued through to the end of the 12-week study period. Patients were instructed to take ERNL at bedtime with a lowfat snack. The study had two aims. One was to assess the safety of ERNL, with particular regard to effects on liver test elevations, creatine kinase (CK) levels, and drug-induced myopathy. The second aim was to evaluate compliance patterns of patients across geographic regions and medical subspecialities.

The dual component lipid lowering agent was generally well tolerated, with flushing being the most common adverse effect, seen in 18% of patients. The incidence of treatment-emergent elevated serum transaminase levels was actually very low, with fewer than 0.5% of patients experiencing alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations greater than three times upper limit of normal. No confirmed cases of drug induced myopathy or rhabdomyolysis were observed. Also, less than 0.5% of patients experienced CK levels greater than five or ten times upper limits of normal.

For the most part, only minor regional and medical subspecialty differences were observed in compliance and reporting of adverse events. Patients in the Southeast region and those enrolled by endocrinologists, however, tended to have the lowest compliance rate and highest rate of reporting adverse events. (McGovern, Mark E. etal. Abstracts of the 52nd Annual Scientific Session of the ACC. Vol. 41 #6 (Suppl A), Pg 245A:1057-221)

Ezetimibe
(Zetia™, Schering-Plough Pharmaceuticals)
Adding ezetimibe, a novel cholesterol absorption inhibitor, to ongoing simvastatin therapy provides significantly greater LDL-cholesterol reduction than doubling the simvastatin dose alone, offering a high efficacious and well tolerated new treatment approach to patients with hypercholesterolemia.

These conclusions were reached from a study designed to evaluate the efficacy and safety of ezetimibe coadministered daily with simvastatin compared to simvastatin alone in patients with heterozygous familial hypercholesterolemia, coronary heart disease, or multiple cardiovascular risk factors. A total of 100 patients were enrolled in this 14-week, Phase III, multicenter, randomized, double-blind, active-controlled, response-based, dose titration study. Initially, these patients underwent dietary stabilization, a 6 to 10 week drug washout period and a simvastatin 20 mg/day open-label run-in period. The patients, all with LDL-cholesterol greater than 130 mg/dL and triglycerides greater than 350 mg/dL while on simvastatin 20 mg, were then randomized to either ezetimibe 10 mg (66 pts) or an additional double-blind dose of simvastatin 20 mg (34 pts). During the course of the study, simvastatin dose was doubled after 4 or 9 weeks of treatment if LDL-cholesterol was still over 100 mg/dL to a maximum of simvastatin 80 mg in the monotherapy group and simvastatin 40 mg in the ezetimibe coadministration group.

The addition of ezetimibe to ongoing simvastatin treatment resulted in nine times as many high-risk patients achieving target LDL-cholesterol levels less than 100 mg/dL at week 14 than simvastatin alone up to 80 mg. At 14 weeks followup, ezetimibe plus simvastatin 20 mg significantly reduced LDL-cholesterol by 24.5% compared to 11.1% in the patients on simvastatin 40 mg monotherapy. Overall, 27% of the coadministration group achieved target LDL-cholesterol less than 100 mg/dL at week 14 compared to 3% of those on simvastatin alone. The safety profile for the coadministration group was similar to that of simvastatin monotherapy. There were no clinically significant changes in vital signs, electrocardiographs, or clinical lab tests including those assessing my muscle and liver function. (Dobs Adrian S etal. Abstracts of the 52nd Annual Scientific Session of the ACC. Vol 41 #6 (suppl A). Pg 227A:1010-147)

Fluvastatin (Lescol®, Novartis)
A new analysis of data from the LIPS (Lescol Intervention Prevention Study) indicates that early fluvastatin treatment in a post-percutaneous coronary intervention (PCI) population with average cholesterol levels reduced the risk of major adverse cardiovascular events (MACE), irrespective of whether stenting or conventional balloon angioplasty was used in the initial PCI procedure.

The LIPS study included 1,677 patients with total cholesterol levels of 135-270 mg/dL and fasting triglycerides levels less than 400 mg/dL. Following successful completion of their first PCI, the patients were randomized to fluvastatin 40 mg twice daily (844 pts) or placebo (833 pts) at hospital discharge. Followup was 3 to 4 years. At least one stent was placed in 1,055 patients (fluvastatin--540, placebo--515) and 582 patients were treated with conventional balloon angioplasty (fluvastatin--287, placebo--295). Primary endpoint of the study was survival time free of MACE, defined as the composite of death, MI, and reintervention--whether PTCA or CABG.

Fluvastatin therapy significantly reduced the subsequent MACE risk by 28% in patients treated with a stent and 39% in patients undergoing balloon angioplasty, compared to placebo, when reinterventions due to restenosis within the first six months of followup were excluded. Within the fluvastatin and placebo groups, there were no significant differences in the lipid profile between balloon angioplasty or stent patients. These findings are consistent with the hypothesis that most of the benefit of statin therapy is derived from effects on the underlying atherosclerotic disease. (Saia, Francesco etal. 52nd Annual Scientific Session of the ACC. Vol 41 #6 (suppl A) Pg 227A:1010-146)

Myocardial Infarction
Enoxaparin (Lovenox®, Aventis)
Enoxaparin, a well-known low molecular weight heparin (LMWH), has been proven to be significantly superior to unfractionated heparin (UH) in reducing ischemic complications in patients with an acute MI treated with fibrinolysis, without substantially increasing major bleeding, even when there was a frequent need for urgent angiography.

To reach these conclusions, a meta-analysis of the data from the ASSENT-3 (Assessment of the Safety and Efficacy of a New Thrombolytic-3), HART II (Low-Molecular-Weight Heparin and Unfractionated Heparin Adjunctive to t-PA Thrombolysis and Aspirin), and ENTIRE-TIMI-23 (Thrombolysis in Myocardial Infarction-23) clinical trials was carried out on 805 patients in the combined data set who underwent urgent angiography on the day of admission. The focus was on death, reinfarction, and refractory ischemia at 30 days in all three trials, and on major bleeding.

Patients treated with enoxaparin had fewer ischemic complications than with unfractionated heparin, as demonstrated by a 20% relative risk reduction in the triple endpoint. Also, there was a major trend toward fewer deaths in the combined data of the three trials. In addition, there was significantly less major bleeding with enoxaparin in the ENTIRE-TIMI-23 trial and comparable rates of major bleeding in enoxaparin and unfractionated heparin in the other two trials. (Sinnaeve Peter R. (Abstracts of the 52nd Annual Scientific Session of the ACC. Vol 41 #6 (suppl A).Pg 334A:1025 MP-171)

Atrial Fibrillation
Ximelagatran (Exanta™, Exanta™, AstraZeneca)
A recently developed, orally administered anticoagulant, ximelagatran, has been shown to be a highly effective alternative to well-controlled warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, not only resulting in a greater reduction of strokes and systemic embolic events in these individuals, but also caused less bleeding while providing a safer, easier-to-administer agent without the need for monitoring.

In the third Stroke Prevention Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF-III trial), an open-label, randomized, non-inferiority trial, a total of 3,407 high-risk patients with atrial fibrillation were randomized to a fixed dose of ximelagatran, 36 mg twice daily or to warfarin, dose adjusted to an INR of between 2 and 3, the mean INR for patients in this arm being 2.5. The patients were maintained on anticoagulation therapy for 12 to 26 months. The primary objective of the study was to establish non-inferiority of ximelagatran versus warfarin for prevention of all strokes, whether ischemic or hemorrhagic, and systemic embolic events, based on intention-to-treat.

In the intent-to-treat followup at 17 months, there were 56 primary events for an annual rate of 2.3% in the warfarin treatment group compared to 40 primary events for an annual rate of 1.6% in the ximelagatran-treated patients, absolute reduction favoring ximelagantran. In the on-treatment followup for those patients remaining on treatment for the full period of the trial, the rates of primary events were 2.2% on warfarin, with 52 strokes and embolic events versus 1.3% on ximelagatran, with 29 primary events, a statistically relative risk reduction of 41%.

With regard to safety, there was a significant reduction in major bleeding events requiring hospitalization in the ximelagatran group (29) compared to those in the warfarin arm (41). There was, however, an increase to greater than three times the upper limit of normal in alanine transaminase (ALT) reported in 6.5% of patients treated with ximelagatran compared to 0.7% of those on warfarin, with all of the enzyme changes occurring within the first six months of treatment. These returned to normal, for the most part, without discontinuing ximelagatran. (Halperin, Jonathan L. etal. 52nd Annual Scientific Session of the ACC. Late-Breaker Clinical Trial #421. Wednesday, April 2, 2003)

Metoprolol CR/XL (Toprol CR/XL®, AstraZeneca)
Metoprolol CR/XL therapy has been shown to provide a better long-term outcome than sotalol (Betapace®, Berlex) or amiodarone (Cardarone®, Wyeth-Ayerst) in maintaining sinus rhythm after successful cardioversion of atrial fibrillation (AF).

Over a five year period from 1997 to 2002, patients after their first recurrence of AF were treated with metoprolol CR/XL at doses of 47 mg to 190 mg daily, sotalol 160 mg to 320 mg daily, or amiodarone at a maintaining dose of 200 mg a day for the first time as long-term therapy after successful electrical cardioversion. Follow-up was continued for a mean three years in all patients for the symptomatic recurrence of AF.

Demographically, patients in all three treatment groups were comparable, with about three-quarters of them being males 62 to 63 years of age, with approximately 60% having organic heart disease. During the three-year study period, 58% (94/161) treated with metoprolol, 71% (163/228) treated with sotalol, and 70% (127/182) treated with amiodarone suffered from symptomatic recurrence of AF. Using a mathematical model, patients treated with metoprolol had a significantly better outcome than those given either sotalol or amiodarone in maintaining sinus rhythm, even when adjusted for age, gender, left atrial diameter greater than 55 mm, and organic heart disease. (Seidi, Kalheinz etal. Abstracts of the 52nd Annual Scientific Session of the ACC. Vol 41 #6 (suppl A) Pg 98A:1089-10)

Heart Failure Nesiritide (Natrecor®, Scios, Inc.)
Nesiritide, a recombinant form of human B-type natriuretic peptide indicated for the treatment of decompensated congestive heart failure (CHF), has been proven to be safe and effective in the treatment of patients under observation in the Emergency Department (ED), with the cost of administrating the drug being offset by decreased costs associated with admission and readmission.

As there has been little investigation done for patients being treated in observation or similarly staffed units, a study was designed to evaluate the safety, efficacy, and economic benefits of nesiritide therapy in the less monitored setting of the ED. In a multicenter, randomized, double-blind, pilot study, 250 patients with decompensated CHF, evidenced by dyspnea at rest or on walking less than 20 feet, were randomized, within three hours of admission to the ED, to either placebo or nesiritide for at least 12 hours. Patients were either admitted or discharged after a maximum of 24 hours in the ED, but could be continued or study drug if admitted into the hospital. Prior to randomization, initial treatment was begun with diuretics, oxygen, and, if desired, morphine or non-parenteral nitrates.

The admission rate for patients receiving nesiritide was 49% vs 55% for patients on placebo. Of hospitalized patients, only 10% of nesiritide-treated patients were re-hospitalized within 30 days compared to 23% of those in the placebo group. The total length of stay in hospital over a 30-day period, including the initial visit for patients hospitalized and then re-hospitalized, was 5.5 days for patients in the nesiritide group versus 10.2 days for those on placebo. There was no significant difference in drug termination, symptomatic hypotension, ventricular arrhythmias, or death between the two patient groups. (Peacock IV, W. Franklin, etal. Abstracts of the 52nd Annual Scientific Session of the ACC. Vol 41 #6 (suppl A). Pg 336:1027-89)

Carvedilol (Coreg®, Glaxo SmithKline)
While the standard combination of ACE inhibition and beta blockade still gives the best results in patients with mild chronic heart failure (CHF), replacement of the ACE inhibitor with the beta blocker carvedilol resulted in a significant reversal of cardiac remodeling, with sustained, long-term reduction in left ventricular (LV) volumes, in contrast to ongoing ACE inhibition alone.

Up to now, in CHF, the effects of beta blockade on mortality, morbidity, and cardiac remodeling have always evaluated in combination with ACE inhibition. To determine whether this combination is mandatory or whether ACE inhibition can be successfully replaced by beta blockade with regard to remodeling, a clinical trial, entitled CARMEN (Carvedilol ACE-Inhibitor Remodeling in Mild Heart Failure Evaluation) was carried out, enrolling 572 mild CHF patients. In this parallel-group, double-dummy, multi-center study, the patients were randomized to carvedilol alone, enalapril alone, or carvedilol plus enalapril, uptitrated on carvedilol to 25 mg twice daily target dose and/or enalapril to 10 mg twice daily target dose and continued for 18 moths. Effects on LV remodeling were assessed by transthoracic echocardiology at baseline and months 6, 12, and 18.

Of the 572 patients in the study, 374 (65%) had been on ACE inhibitor treatment prior to the start of the study, while only 6% were on beta blockade. A subgroup analysis of the primary endpoint in former ACE inhibitor users showed that LV end-systolic volume index was reduced at month 18 by 4.7 ml/m2 in the patients on carvedilol alone and by 6.0 ml/m2 in the carvedilol plus enalapril treated patients from baseline. In contrast, in the patients who received only enalapril, the LV end-systolic volume index was increased by 0.6 ml/m2. Despite a change in therapy, carvedilol-treated patients did not experience more adverse effects and a similar number of patients in each of the three arms of the study completed the trial. (Remme, Willem J. Abstracts of the 52nd Annual Scientific Session of the ACC. Vol 41 #6 (suppl A). Pg 205A:1184-73)

Conclusion
Cardiovascular disease still remains a major public health problem worldwide but continuing research is producing new, more effective inroads in the treatment, control and prevention of a wide range of cardiac disorders. This is especially evident as one sees standards of care improving while rates of mortality and morbidity are reduced in the area of cardiovascular medicine. Of particular importance is the fact that even more positive developments are just around the corner, offering greater hope in the future.