NEWS & VIEWS

Progress in Interventional Cardiology

This issue of News & Views: Progress in Interven- tional Cardiology will focus on developments pre- sented prior to and at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Georgia, USA, November 8-10,1999, Areas of focus include pharmacological therapy to modify lipid profiles and the ongoing controversy on optimal medical manage- ment of chronic heart failure.

Raising High-Density Lipoprotein Levels to Prevent Atherosclerotic Events

For patients with elevated serum cholesterol, atherosclerotic risk modification has focused on re- ducing elevated low-density lipoprotein cholesterol (LDL-C). ’ Several clinical trials show that reducing elevated LDL-C results in lower rates of myocardial infarction, stroke, coronary revascularization proce- dures, and death.2-4 Frequently however, “normal” LDL-C concentrations are coupled with low high-den- sity lipoprotein cholesterol (HDL-C) levels in patients with coronary heart disease. In one study of 8,500 pa- tients with coronary heart disease, 41 % had isolated low HDL-C (< 35 mg/dL) level^.^ Until recently, op- timal treatment of this group had not been defined. There is now an accumulating body of evidence of the treatment benefit in these patients to reduce the occur- rence of myocardial infarction or other cardiovascular events.

Air ForceITexas Coronary Atherosclerosis Prevention Study. The first trial supporting the benefit of raising low HDL-C levels comes from the Air Force/Texas Coronary Atherosclerosis Pre- vention Study (AFCAPS/TexCAPS).6 In this placebo-controlled trial, lovastatin 20-40 mg daily was administered to males and females without evi- dence of coronary heart disease, low to normal HDL-C, and slightly elevated LDL-C (Table 1). When the study was completed, lovastatin had in- creased HDL-C levels by 6% and lowered LDL-C by 25%. In this relatively low risk population of indi- viduals, lovastatin reduced the rate of first coronary heart disease event (fatal and nonfatal myocardial in-

farction, unstable angina pectoris, sudden cardiac death) by 37%. However overall mortality was simi- lar between treatment and placebo groups. Impor- tantly, benefits of therapy were observed predomi- nately for patients whose HDL-C levels were lowest (< 40 mg/d).7

Veterans Administration High-Density Lipo- protein Cholesterol Intervention Trial. Support- ing evidence emanates from the Veterans Admini- stration High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT).’ The hypothesis of this trial was to determine if raising HDL-C and lowering triglyceride concentrations would reduce the incidence of death from coronary heart disease and nonfatal myocardial infarction in patients with known coronary heart disease. The study was a dou- ble-blind comparison of gemfibrozil 1,200 mg daily versus placebo in males with HDL-C 5 40 mg/dL, LDL-C I 140 mg/dL, and triglyceride of 5 300 mg/dL. The median follow-up for 2,53 1 men was 5.1 years. Average lipid profile values, before and after gemfibrozil treatment, are presented in Table 1. Gem- fibrozil therapy increased HDL-C by 6% and reduced nonfatal myocardial infarction and coronary heart dis- ease death by 22%. All-cause mortality was similar between groups.

Therapy was well tolerated in both studies. In AF- CAPSRexCAPS, there were similar rates of serious and minor adverse events in the lovastatin and place- bo groups. In VA-HIT, gemfibrozil-treated patients had significantly more gastrointestinal complaints than those assigned placebo, but compliance was not affected.

It is now appropriate to consider both high LDL-C and low HDL-C when treating patients with coronary heart disease. Initial therapeutic targets include lifestyle modification (smoking cessation, weight loss, aerobic exercise, diabetes mellitus control) to increase the HDL-C and to avoid prescribing drugs (thiazide di- uretics, p-adrenergic blockers) that decrease HDL-C. When these interventions are not sufficient, there is now evidence supporting the use of medications to raise the low HDL-C to reduce the occurrence of my- ocardial infarction and death.

Vol. 13, No. 1, 2000 Journal of Interventional Cardiology 73

JOSEPH, ET AL.

Table 1. Average Lipid Profiles Before and After Treatment of Patients in VA-HIT and AFCAPSRexCAPS

VA-HIT AFCAPSmexCAPS

Before After Before After Treatment Treatment Treatment Treatment

Total cholesterol (mg/dL) 175 170 22 1 184 Triglycerides (mg/dL) 161 115 158 143 HDL-C (mg/dL) 32 34 36 39 LDL-C (mg/dL) 111 113 150 115

Angiotensin I1 In Heart Failure: More Results, More Confusion

Angiotensin converting enzyme (ACE) inhibitors are the drugs of choice in the treatment of heart failure. However, the mechanism of benefit remains a mystery. ACE inhibitors have the dual role of inhibiting the con- version of angiotensin I to I1 and decreasing inactiva- tion of bradylunins.' Yet, in the human left ventricle, the conversion of angiotensin I to I1 is primarily medi- ated by the proteolytic enzyme chymase, not ACE."

Angiotensin I1 interacts with type 1 and 2 cellular receptors. (There are also type 3 and 4 receptors of un- certain significance.) Deleterious consequences on the myocardium are regulated primarily through an- giotensin I1 interaction with the type I receptor (Fig. l), which includes vasoconstriction, proliferation of smooth muscle cells, myocyte hypertrophy, and po- tentiation of other neurohormones, especially nore- pinephrine and aldosterone.' The type 2 receptor has opposing actions including vasodilation and antiprolif- eration. Commercially available angiotensin receptor blockers (ARBs) selectively block the adverse effects of angiotensin I1 on the type 1 receptor. The conse- quent increase in angiotensin I1 levels may lead to overstimulation of the type 2 receptor, with possible beneficial effects.

Therefore, the differential effects of ACE inhibition compared to ARBs are

-ACE inhibition leads to incomplete suppression of angiotensin I1 production with reduction of stimula- tion of type 1 and type 2 receptors. Levels of bradykinin and prostaglandin are elevated.

-ARBS lead to more complete suppression of an- giotensin I1 effects on the type 1 receptor, with pos- sible overstimulation of type 2 receptor.

-Combination therapy with ACE inhibitors and ARBs theoretically allows more complete suppres-

sion of effects of angiotensin I1 on type 1 receptor, with elevation in bradykinin levels.

The first large scale study to test these differences was the phase 2, Evaluation of Losartan in Elderly (ELITE) study." In this study, 722 elderly patients with systolic left ventricular dysfunction and symp- tomatic heart failure were randomized to receive losar- tan or captopril. The primary endpoint of the ELITE study was the incidence of persistent renal dysfunction determined after 48 weeks of therapy. While there was no statistically significant difference in the occurrence

Angiotmsinop.n

ACE lnhibitm

Angbtenskr II Inactive mtablites

ARB ATlR AT2R

1 1 Inueased afterload Promotes apoptosir

Myocyte loo8

Myourdiol flbrosls

Potentiates sMosterone

Potentiates norephphrim

AntiClbrotlc

Figure 1. Renin-angiotensin-aldosterone system with reference to the actions of angiotensin converting enzyme inhibitors and angtiotensin receptor blockers. ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; ATlR = angiotensin I1 type 1 receptor; AT2R = angiotensin I1 type 2 receptor.

74 Journal of Interventional Cardiology Vol. 13, No. 1,2000

Table 2. Preliminary Results of the Evaluation of Losartan in Elderly Study-I1

Total mortality Cardiovascular mortality

Sudden death Heart failure

Noncardiovascular mortality Sudden death/resuscitated arrest Total hospitalization Hospitalizations related to

heart failure

NEWS AND VIEWS

Vol. 13, No. 1,2000 Journal of Interventional Cardiology

Captopril (n = 1578)

250 (15.9%) 199 (12.6%) 101 (6.4%) 53 (3.4%) 51 (3.2%)

115 (7.3%) 638 (40.5%) 293 (18.6%)

Losartan (n = 1574)

280 (17.7%) 230 (14.6%) 130 (8.2%) 46 (2.9%) 50 (3.2%)

142 (9.0%) 659 (41.8%) 270 (17.1%)

of renal dysfunction between the agents, losartan was better tolerated than captopril. Interestingly, there was a 46% reduction in all-cause mortality (losartan 4.8% vs captopril 8.7%, P = 0.035) and a 64% decrease in the occurrence of sudden death. Armed with these fa- vorable results, the phase 3 ELITE I1 trial was de- signed to determine differential clinical benefit be- tween the agents.

The results of the ELITE I1 were presented at the 72"d Scientific Sessions of the American Heart Asso- ciation, Atlanta, Georgia, USA, November 8-10, 1999 (Table 2).'* Patients in the ELITE I1 study were > 60 years of age with New York Heart Association Class 11-IV heart failure and left ventricular ejection fraction < 40%. A total of 3,152 patients received captopril 50 mg three times daily (n = 1,574) or losartan 50 mg daily (n= 1,578). The primary end- point, determined 2 years after randomization, was all-cause mortality. Secondary endpoints included sudden cardiac death or resuscitated cardiac arrest, all-cause mortality or hospitalizations, safety, and tolerability.

With a median follow-up of 1.5 years, there were no significant differences in prespecified outcomes between those patients who received captopril or losartan. These results ran counter to those of ELITE I, yet, ELITE I1 confirmed the earlier result that losar- tan was better tolerated with fewer discontinuations due to side effects. With overwhelming positive re- sults from numerous clinical studies using ACE in- hibitors in patients with heart failure, the main clini- cal message from ELITE I1 is that ARBS offer a safe alternative in patients with heart failure who are in- tolerant or have a contraindication to the use of ACE inhibitors.

1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the National Choles- terol Education Program Expert Panel on Detection, Evalua- tion, and Treatment of High Blood Cholesterol in Adults. JAMA 1993;269:3015-3023.

Intriguing questions remain:

-1s it important to effect complete blockade of an-

-Are there any unforeseen harmful effects of over-

-Are there significant beneficial effects of

-If so, would the combination of ACE inhibitors and

giotensin I1 production?

stimulation of type 2 receptor?

bradykinins in heart failure?

ARB be found to be more effective?

Ongoing studies may shed light in these areas. The Valsartan Heart Failure Trial (ValHeFT) is evaluating the effect of ACE inhibitors/ARB versus ACE in- hibitors/placebo in patients with chronic heart failure. Another trial with valsartan, the Valsartan in Acute Myocardial Infarction Trial (VALIANT), evaluates the efficacy of valsartan alone and in combination with captopril versus captopril alone in patients postmy- ocardial infarction with heart failure or left ventricular systolic dysfunction. Candesartan is being evaluated for heart failure in the Candesartan Cilexetil in Heart Failure Assessment of Reduction of Mortality and Morbidity (CHARM) trial. This trial includes not only patients with systolic dysfunction on ACE inhibition, but also patients who are ACE inhibitor intolerant and those with heart failure and preserved systolic function.

The next News & Views: Progress in Interventional Cardiology will focus on additional developments in the field of interventional cardiac care.

Jacob Joseph, M.D. Assistant Professor of Internal Medicine

Director, Heart Failure Treatment Program University of Arkansas for Medical Sciences

Jorge Saucedo, M.D. Assistant Professor of Internal Medicine

Director, Cardiac Catheterization Laboratories University of Arkansas for Medical Sciences

J. David Talley, M.D. Professor of Internal Medicine

Director, Division of Cardiology University of Arkansas for Medical Sciences

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