NEWS &VIEWS

Progress in Interventional Cardiology

This issue of News & Views: Progress in Interven- tional Cardiology will focus on developments pre- sented at the XXIst Congress of the European Society of Cardiology, (Barcelona, Spain, August 28-Septem- ber 1, 1999), the Third Annual Scientific Meeting of the Heart Failure Society of America (San Francisco, California, USA, September 22-25, 1999), and the Eleventh Annual Symposium of Transcatheter Cardio- vascular Therapeutics (TCT) Conference, (Washing- ton DC, USA, September 22-26, 1999). Areas of fo- cus include pharmacological therapy to ameliorate myocardial ischemia, medications used in the treat- ment of chronic heart failure, and the vexing problem of restenosis after percutaneous coronary intervention.

ACE Inhibitors as Anti-ischemic Medications

Advances in basic and clinical investigation point to the endothelium as a link between pathological pro- cesses and clinical events in the pathogenesis of acute ischemic coronary syndromes. Diagnostic methods have been refined to evaluate endothelial function. Acetylcholine infused directly into a normal coronary artery causes vasodilatation. Failure to dilate or “para- doxical vasoconstriction” is seen with acetylcholine infused into atherosclerotic arteries. Of interest, an- giotensin converting enzyme (ACE) inhibitors im- prove endothelial function and therefore may, in part, be considered an anti-ischemic medication.

Ramipril. The effects of inhibiting-tissue ACE were examined in the Heart Outcomes Prevention Evaluation (HOPE) study, the results of which were presented at the XXIst Congress of the European So- ciety of Cardiology in Barcelona, Spain. A total of 9,541 patients enrolled from 267 centers in 19 coun- tries with known coronary artery or peripheral vascu- lar disease, stroke, or diabetes (with another risk fac- tor) were included in the HOPE trial. Slightly more than half (54%) of the patients were normotensive. HOPE had a 2 X 2 factorial design; patients received ramipril (Altace, Hoechst Marion Roussel) 2.5 mg titrated to 10 mg or placebo andor Vitamin E 400 IU. The primary end point, determined after 4 years of fol-

low-up, was the combination of death from cardiovas- cular causes, myocardial infarction, or stroke. HOPE was halted early because of the overwhelmingly posi- tive results in the ramipril-treated patients. The benefit results were consistently positive across multiple end points pointing to the potential benefit of this combi- nation of therapy on a broad population of patients at high risk for cardiovascular events (Fig. 1). There was no benefit with the use of Vitamin E (composite of death, myocardial infarction, or stroke occurred in 16% of patients who received Vitamin E and 15.4% of those who received the placebo).

Future Directions. There are several additional tri- als of ACE inhibitors underway for treatment of coro- nary artery disease in patients with normal left ven- tricular systolic function.’ These trials include the Pre- vention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) using trandolapril (n = 8,100, anticipated completion date late 2003) and Eu- ropean Trial of Reduction of Cardiac Events with Perindopril in Stable CAD (EUROPA) using perindo- pril (n = 10,500, anticipated completion date, late 2002). These studies attempt to decipher the interrela- tionship between multiple diverse properties of ACE inhibitors, including restoration of oxygen demand/supply ration, neurohormonal modulation, restoration of endothelial function, antithrombotidan- tiplatelet effects, and antiatherogenic/antiproliferative properties.

Adrenergic Blockade in Heart Failure: Pros and MOXCON

The benefit of P-adrenergic blockade to reduce morbidity and mortality in heart failure is now proven with the publication of the results of three successive large scale clinical trials using selective and nonselec- tive P-blockade. These trials confirm the neurohor- monal hypothesis in the pathogenesis of chronic heart failure. Yet, at the recently concluded Heart Failure Society of America meetings in San Francisco, results from the SR Moxonidine for Congestive Heart Failure (MOXCON) study highlight the continuing evolution

Vol. 12, No. 6, 1999 Journal of Interventional Cardiology 521

JOSEPH, ET AL.

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CVDDeath Non-FafalMI Stroke CABGiPTCA NewOnset Dubeles

Figure 1. Relative risk reduction of the component of the primary end point of the Heart Outcomes Prevention Evaluation (HOPE) study. There was a clear-cut reduction of these events in patients who were treated with ramipril compared to those who receive placebo. CABGtPTCA = coronary artery bypass graft surgery/percutaneous transluminal coronary angioplasty; CVD =

cardiovascular death: MI = myocardial infarction.

of our understanding of the etiology of chronic heart failure.

Chronic heart failure is due in part to hyperactivity of the sympathetic nervous system.* There is a pro- nounced linkage among plasma norepinephrine levels, clinical status, and adverse prognosis in chronic heart failure.324 Two alternative explanations were proposed for this seminal observation. First, the elevation in norepinephrine levels may have directly contributed to progression of heart failure. Alternatively, plasma norepinephrine may have been an indication of wors- ening heart failure independent of adrenergic activa- t i ~ n . ~ Nonetheless, the results of these studies fueled the neurohormonal hypothesis in the pathogenesis of patients with chronic heart failure.

Moxonidine is structurally related to clonidine and acts on central imidazoline receptors in the medulla to decrease sympathetic o ~ t f l o w . ~ This medication is ef- fective and safe in the treatment of essential systemic arterial hypertension and has a side effect profile bet- ter than clonidine.6 The acute hemodynamic and neu- rohumoral effects of moxonidine in chronic heart fail- ure was examined by Dickstein et al.7 Patients with chronic heart failure (n = 32) in New York Heart As- sociation (NYHA) Class I11 were enrolled in a double- blind, dose-ranging study to receive placebo or 0.2- mg, 0.4-mg, or 0.6-mg single oral doses of moxoni- dine. Invasive hemodynamic monitoring and measurements of plasma norepinephrine were per- formed after randomization. All patients were on chronic therapy with an ACE inhibitor, digoxin, and

diuretics. Moxonidine produced dose-dependent fa- vorable effects over 6 hours on hemodynamic param- eters including mean pulmonary and systemic arterial pressures, vascular resistances, and heart rate. Addi- tionally, the plasma norepinephrine was reduced sub- stantially by - 180 pg/mL at 4 hours (P < 0.005). This study showed the hemodynamic benefits of reducing sympathetic activation by a centrally acting sympa- tholytic drug.

The MOXCON study evaluated the effect of sus- tained-release moxonidine (Eli Lilly and Company, Indianapolis, IN, USA) on mortality and morbidity in patients with chronic heart failure. This was a random- ized, double-blind, placebo-controlled, multicenter study in patients with NYHA Class 11-IV chronic heart failure and left ventricular ejection fraction < 35%.8 The study was divided into six phases: screen- ing and lead in, randomization, dose optimization (pa- tients were titrated from 0.25 mg bid to the maximum tolerated dose up to 1.5 mg bid), maintenance, dose ta- pering, and washout. The dose-tapering and washout phases were designed to assess the risk of rebound phenomena on stopping the drug as witnessed during clonidine therapy. The primary end point was all- cause mortality. Use of P-adrenergic blockade was an exclusion criterion initially.

The study enrolled 1,933 patients in 1.5 years equally distributed between the placebo and moxoni- dine groups. Patients were predominantly in NYHA Class I1 and 111, baseline left ventricular ejection frac- tion approximating 25%, and plasma norepinephrine values ranging between 440-460 pg/mL. The study was terminated after 1 year of follow-up due to exces- sive deaths in the moxonidine group (5.4% vs 3.1% in placebo group) (Table 1). There was no increase in deaths during the dose-tapering period, indicating that the effect may not be due to inadvertent cessation of

Table 1. Mortality Statistics in the MOXCON Trial

Placebo Moxonidine Total (n = 944) (n = 989) (n = 1,933)

All-cause mortality 29 (3.1%) 53 (5.4%) 82 (4.2%) Sudden death 11 (1.2%) 26 (2.6%) 37 (1.9%) Death from pump failure 9 (0.9%) 15 (1.5%) 24 (1 2 % )

As presented by Cohn JN. MOXCON study results. Presented at the Heart Failure Society of America Meetings, San Francisco, CA, September 22-25, 1999.

MOXCON = SR MOXonidine for CONgestive Heart Failure.

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NEWS AND VIEWS

therapy. There was an increased incidence of sudden death and death due to pump failure. The most inter- esting aspect of the results was that moxonidine pro- duced a significant decrease in plasma norepinephrine levels in survivors and those who succumbed.

How do we interpret these results? Although this study may have been negative by chance, there could have been an unknown adverse effect at this dose range of the drug, leading to excess mortality. It is pos- sible that adrenergic activity was reduced below phys- iological levels or too rapidly. Alternatively, since the neurohumoral axes are interrelated, a large rapid de- cline in adrenergic drive in the presence of heart fail- ure may have set off inappropriate activation of other systems with adverse consequences on cardiovascular homeostasis.

Update of Brachytherapy from TCT XI

Endovascular radiation therapy for the treatment or prevention of restenosis may become the next break- through in the field of interventional cardiology. Re- sults from the GAMMA-1 trial were presented at the Transcatheter Cardiovascular Therapeutics (TCT) Eleventh Symposium in Washington DC.9 GAMMA- 1 was a multicenter, randomized trial of localized ra- diation therapy to inhibit restenosis after stenting. This was a placebo-controlled trial using Iridium 192 that enrolled 252 patients from 12 centers from December 1997 to July 1998. There were two primary end points of the trial: (1) the composite incidence of death, my- ocardial infarction, and target lesion revascularization, and (2) the incidence of binary restenosis determined angiographically at 9 months.

Clinical characteristics and procedure variables were similar in both groups, except more patients in the ra- diation group had lesions treated in the left anterior de- scending coronary artery than the placebo arm (45% vs 3 1 %, P = 0.02). In-hospital major adverse events were similar between groups (placebo: 3.3%, radiation 2.3%, P = 0.6). Nine months after randomization, ad- verse clinical events were decreased in patients who re- ceived radiation (Table 2). There was also a dramatic reduction in the occurrence of restenosis in the radia- tion group. In-stent restenosis was deceased from 51% in the placebo group to 22% in the radiation group (P = 0.005, relative risk reduction 57%) and in-lesion restenosis was cut from 53% in the placebo group to

Table 2. Key Results from the GAMMA-I Trial

Placebo Iridium 192 P Value

Number of patients 121 131 Composite of death, 44% 28% 0.01

myocardial infarction, target lesion revascularization

Death 1% 3% 0.2 Target lesion 42% 24% 0.003

Stent closure 2% 7% 0.006

As presented by Leon MB. Results from the GAMMA 1 trial. Pre- sented at Transcatheter Cardiovascular Therapeutics, Eleventh An- nual Symposium. Radiation Vascular Therapy for the Intervention- alist, Washington DC, September 22, 1999.

revascularization

32% in the radiation patients (P = 0.01, relative risk re- duction 41%). While there was a dramatic decrease in the occurrence of major adverse clinical events and an- giographic restenosis with the use of radiation, there was a worrisome trend of higher death rate and more stent closure at follow-up in patients treated with radi- ation therapy. The mean time of stent closure was 4.6 months following radiation administration.

Late thrombosis of the radiation-treated site is an emerging “new” disease in the field of interventional cardiology. Waksman and colleagues using “pooled” data in patients enrolled into ‘trials using radiation at the Washington Hospital noted an incidence of late thrombosis of 9% in patients treated with radiation compared to 1% in patients in the “control arm.”” More than 80% of patients who presented with late thrombosis had new stents deployed at the time of ra- diation administration. Late thrombosis is not a subtle event. More than 90% of patients presented with an acute ischemic coronary event (43% acute myocardial infarction, 50% with unstable angina pectoris). In an effort to address this problem, antiplatelet drugs are being given for a longer period of time (up to 6 months) and standard balloon angioplasty is the pre- ferred method of revascularization.

Despite the palpable excitement of the interven- tional cardiology community for the adjunct use of ra- diation therapy in the percutaneous treatment of coro- nary artery disease, the details of this approach need to be teased out prior to its widespread dissemination into clinical practice.

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JOSEPH. ET AL.

The next News & Views: Progress in Interventional Cardiology will focus on developments presented prior to and at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Georgia, USA, November 8-10, 1999.

Jacob Joseph, MD Assistant Professor of Internal Medicine

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

Jorge Saucedo, MD Assistant Professor of Internal Medicine

Director, Cardiac Catheterization Laboratories University of Arkansas for Medical Sciences

J. David Talley, MD Professor of Internal Medicine

Director, Division of Cardiology University of Arkansas for Medical Sciences

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