Clin. Cardiol. 21,429-431 (1998)

Progress in Clinical Trials

PACT (Plasminogen Activator and Angioplasty Compatibility Wal)

Presenter

Allan Ross, M.D., at the 47th Scientific Sessions of the American College of Cardiology, Atlanta, Georgia

significant extent than among those who required an angio- plasty to achieve TlMI grade 3 flow.

TPA (50 mg) therapy produced a significantly higher in- farct artery patency rate prior to cath lab arrival asyociated with measurably improved ventricular function at discharge. Pretreatment with study drug did not diminish technical an- gioplasty succes5. There were no complications ascribable to this combination approach.

Background Conclusion

Studies have tested and rejected the combination of throm- bolytic therapy and angioplasty. However, the small Strep- tokinase Angioplasty Myocardial Infarction (SAMI) study comparing true, primary angioplasty with lysis (via intraven- ous streptokinase, a long-acting, systemic fibrinolytic) and then truly immediate rescue angioplasty. achieved high suc- cess with percutaneous transluminal coronary angioplasty (PTCA) in the lytic group, although with significant bleeding.

Preliminary thrombolytic therapy followed by immediate backup rescue angioplasty appears to have considerable advantage over pure primary angioplasty while showing no evident drawbacks. This approach will be the optimal one among available current reperfusion methods for a very large segment of the population of patients with MI.

Purpose ACADEMIC (Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with chlamydia)

Presenters

The PACT study is a repeat comparison of primary angio- plasty versus fibrin-selective, short-acting thrombolytics fol- lowed by truly immediate angioplasty, ifrequired.

JeffrevL. Anderson, M.D., and Joseph 6. Muhlrstein, M.D., Study Population

at the 47th Scientific Sessions of the Aimencan College of Car- diology, Atlanta, Georgia The randomized, placebo-controlled study evaluated 606

patients with acute myocardial infarction (MI) within 6 hours of symptom onset. All were free of cardiovascular disease, over age 75, with no previous coronary artery bypass graft Background

surgery.

Study Design

Patients received aspirin and intravenous unfractionated heparin. were randomized to a 50 mg bolus of tissue plas- minogen activator (TPA) or placebo, and then went to the car- diac catheterization laboratory for angiography. Immediate angioplasty was performed on those with vessel flow of TIMI (Thrombolysis in Myocardial Infarction) grades 0 to 2. A sec- ond bolus of study drug or placebo was given to those with TIM1 grade 3 flow. Patients underwent an angiogram and a ventriculogram after one week, and a symptom-limited exer- cise test after six weeks. The prespecified principal efficacy end point was predischarge ejection fraction (EF) from a con- trast ventricu I ograin .

Studies have indicated a possible role of Clikitiiydici p t i w mnniue in atherosclerotic disease. Two pilot studies have reported a reduction in cardiovascular events after adminis- tration of azithromycin and roxithromycin, respectively, to control C. pneimnionicie.

The ACADEMIC trial is a double-blind, randomized sec- ondary prevention trial to test whether azithrornycin reduces systemic markers of inflammation, antibody titers to Cklimz- ydia and vascular events in patients with symptoniatic coro- nary artery disease (CAD).

Study Population

Results The study evaluated 302 patients over age 18 with previ- ous MI or angiographically demonstrated CAD, life expect- ancy of > 2 years and an IgG titer to CIilrir7iydio of at least 1 to 16. Fifty patients were randomized to azithromycin, and 1 SO to placebo.

Patients with early (cath lab) TIM1 grade 3 flow due to com- bined spontaneous lysis, anticoagulation and TPA left the hos- pita1 with mean ejection fraction of 6256, higher to a highly

430 Clin. Cardiol. Vol. 21, June 1998

Study Design

Patients received azithromycin (500 mg/day for 3 days, then once weekly for three months on an empty stomach) or matching placebo. The primary laboratory end point was a combined analysis at 3 months of four inflammation markers: C/?/LimvctiLz-reactive protein, interleukin- 1 and -6, and tumor necrosis factor (TNF). The secondary end point was reduc- tion of anti-Chlamydia IgG titers at 6 months. The clinical end points were a reduction in composite cardiovascular events at 6 months (secondary end point) and two years (pri- mary end point).

Results

At 3 months, azithromycin did not significantly reduce the combined systemic inflammation markers. By 6 months, however, there was a statistically significant stabilization of CIiI~iiii~diu-reactive protein and IL-6, and a trend toward stabi- IiLation of IL-1. Azithromycin showed no effect on TNF activity and did not significantly affect IgG or IgA antibody titers at 3 or 6 months. Interim, 6-month clinical events were uncommon and did not differ between groups. Azithromycin wa\ well tolerated and infections were reduced during the 3 months of administration in the treatment group.

Conclusion

The marked reduction in cardiovascular events report- ed i n the small pilot studies appears to be overly optimis- tic. ACADEMIC’S primary laboratory end point was not achieved at 3 months, but clinical events have yet to sepa- rate. Larger, longer-term studies will be required to assess the impact of azithromycin on clinical events. The positive effects of azithromycin on Chlamydia-reactive protein and IL-6 at 6 months are provocative and should stimulate fur- ther research.

Stent PAMI (Primary Angioplasty in Myocardial Infarction)

Presenter

Cindy L. Grines, M.D., at the47th Scientific Sessions of the American College of Cardiology, Atlanta, Georgia

Background

While primary angioplasty has shown itself to be far superi- or to thrombolytic therapy, primary angioplasty is subject to residual stenosis and dissections that are predictive of recur- rent ischemia, reocclusion, and possibly late restenosis.

Purpose

The purpose of Stent PAMl was to compare primary stent- ing with the Palmaz-Schatz heparin-coated stent and primary angioplasty in acute MI.

Methodology

Patients included in the 900-patient study (heparin-coated Palmaz-Schatz stent, 452; PTCA, 458) were enrolled less than 12 hours after the onset of acute myocardial infarction ( M I ) symptoms. After suboptimal results, 67 PTCA pa- tients (1 5. l %) crossed over to stent procedures. Multivessel disease was found in 44% of patients overall. Nearly all pa- tients (99%) received adjunctive aspirin and around 90% re- ceived ticlopidine in both groups.

Procedural success was achieved among 98.7% of patients with stents and in 84.9% of patients who underwent PTCA. In U.S. core lab assessments, percent stenosis was measured at 12% for stenting and 24% for PTCA. Minimal luminal di- ameters post procedure were significantly larger for the stent- ed group (2.55 vs. 2.1 1 mm). TIM1 grade 3 flow was reported in a slightly but not significantly higher percentage (96.4 vs. 92.9) of patients who underwent PTCA.

In-hospital, recurrent chest pain with ST segment eleva- tion was reported in fewer stented patients ( I .2 vs. 3.5%). ischemia-driven target vessel revascularization (TVR) was required in fewer stented patients (0.6 vs. 2.5%), and hospital stays (U.S. only) were shorter for stented patients (4 vs. 5 days). Combined ischemic measures, however, were not dif- ferent between the two groups.

At 1 month, combined death, recurrent MI, disabling stroke, and ischemic TVR were similar for the groups (4.2% for stent- ing, 5.4% for PTCA). Only TVR was significantly lower for the heparin-coated stent (0.9 vs. 3.5%).

Conclusion

Compared to primary PTCA for AMI, use of the Palmaz- Schatz heparin-coated stent resulted in greater lumen size and reduced early ischemia-driven TVR, but did not influence the composite primary end point at 1 month. Six-month results will be available in the Fall of 1998.

Comment

Dr. Grines stated: “One factor improving PTCA results is that all of the suboptimal PTCA cases were crossed over to stenting.”

ATLAS (Assessment of Treatment with Lisinopril and Survival)

Presenter

Milton Packer, M.D., at the 47th Scientific Sessions of the American College of Cardiology, Atlanta, Georgia

Clinical Trials 43 1

Background

In prior major clinical trials demonstrating the value of angiotensin-converting enzyme (ACE) inhibitor therapy in heart failure that led to its gradual adoption worldwide, doses were 4-6 times higher than those used subsequently in clini- cal practice.

purpase

This trial was undertaken to assess the effects of low- and high-dose lisinopril on major clinical events among patients with moderate-to-severe heart failure (ejection fraction 30%) despite conventional therapy.

Study Population

Total population was 3,164. Most patients had class III New York Heart Association (NYHA) symptoms and 90% had been taking ACE inhibitors before enrollment.

Methodology

Patients were titrated to low-dose (2.5-5.0 mg daily, n = 1,568) or high-dose (32.5-35 mg daily, n = 1,596) lisino- pril, doses that closely match typical clinical practice on one hand, and the target doses of ACE inhibitor clinical trials on the other.

The primary end point was all-cause mortality. The primary secondary end point was the combined risk of death and hos- pitalization for any reason.

RWllts

There was a nonsignificant 8% reduction in all-cause mor- tality for the higher lisinopril dose and a trend (10% reduction) in cardiovascular death (642 low dose vs. 583 high dose). Disease progression measured through all-cause death or hos- pitalization occurred less often in the lisinopril group to a high- ly significant extent (1,339 events for the low dose, 1,25 1 for high dose, a 12% reduction, p = 0.002). Morbidity was signif- icantly reduced in the high-dose group, across all-cause, car- diovascular, and heart failure definitions.

Cough was less common in the high-dose group. Other side effects characteristic of angiotensin suppression were some- what more common in the high-dose group, but did not require discontinuation of treatment.

Conclusion

Low ACE inhibitor doses produce about 50% of the treat- ment effect seen with high doses.

Comment

A physician has as much reason to increase the dose of an ACE inhibitor from low to high as he or she has in starting an ACE inhibitor and maintaining it at a low dose. Dr. Packer ex- pressed concern that physicians will assume that they can achieve the results demonstrated in the ATLAS trial with just a small or moderate increase in ACE doses, warning “We just don’t know if that’s true.”

TOSCA (Total Occlusion Study of CAnada)

Presenter

Christopher E. Buller, University of British Columbia, Vancouver, Canada

Background

Long-term results of PTCA are poor in total occlusions.

p w o s e

The purpose of TOSCA was to determine whether primary stenting of a broad, relatively unselected spectrum of nonacute coronary occlusions improves sustained patency, 6-month tar- get lesion lumen dimensions, and one-year clinical outcome compared with primary balloon angioplasty (PTCA).

Methodology

After a guide wire was advanced across the occlusion, but before initial balloon inflations, patients (n = 410) were ran- domized to heparin-bonded Palmaz-Schatz stents or to prima- ry PTCA. Patients received aspirin plus ticlopidine. Long le- sions were not excluded.

Patient Population

Most lesions required two or more stents and a third of pa- tients underwent multivessel procedures.

Results

Final MLD was larger for the stent group (1.48 vs. 1.23 mm). More PTCA patients than stent patients (19.5 vs. 10.9%, p = 0.024,8.6% absolute risk reduction, relative risk of 44%) reached the primary end point of failure of sustained pa- tency (TIMI flow < 3) within six months accompanied by sig- nificant stenosis (96% angiographic follow-up). The largest reduction was seen in recurrence of TIMI grade 0 flow. No benefit for stenting was reported for occlusions of 6 weeks du- ration, however. Although restenosis values at follow-up were high (70% for PTCA, 56% for stent), target vessel revascular- ization was low (13.9% PTCA vs. 7.4% stent, p = 0.038), in- dicating that a substantial degree of renarrowing is clinically well tolerated in previously occluded vessels. While small, periprocedural infarcts [<5 X creatine kinase (CK) rise] were higher in the stented group (5.4 vs. 1 .O%), MIS (5 X CK rise) were relatively rare (9 in the stented group, 4 in the PTCA group, NS). Ejection fractions, however, were significantly higher at follow-up among stented patients.

Conclusion

Compared with PTCA, primary stenting of total coronary occlusions resulted in improved 6-month patency, larger lu- men dimensions, reduced restenosis and need for target vessel revascularization. Based upon these observations, investiga- tors offered a preliminary clinical recommendation that pri- mary stenting of symptomatic nonacute coronary occlusions is indicated when percutaneous recanalization is performed.