Efficacy of revascularization when compared to medical therapy in patients with stable and unstable coronary artery disease

A comparison among the risks of the natural course of coronary artery disease placed into perspective with the results of recently reported trials having investigated hard end-points in revascularized patients with coronary artery disease.

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Stable coronary syndromes     


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The following discussion addresses specifically the questions, whether

patients treated with revascularization have a better outcome in terms of cardiac death and acute myocardial infarction than medically treated patients, if

coronary angiography is a reliable tool to predict the functional severity and prognostic impact of coronary narrowing and the caveats we should know from the presence of coronary thrombus in patients undergoing revascularization and

what might be the impact of non-invasive stress testing in patients with known or suspected coronary artery disease.

Placing the success achieved by revascularization in perspective with the natural course of coronary artery disease derived from historical groups of patients with known coronary anatomy and normal or near normal left ventricular function, the net benefit in terms of risk reduction for cardiac death and acute myocardial infarction appears not quite impressive. Especially in low to medium risk patients treated with Stents/PTCA further randomized studies are urgently needed, in order to establish, which patients may benefit from revascularization.

This review, however,  excludes patients with severely impaired left ventricular function (e.g.< 30%), a subgroup of patients, for whom revascularization (especially  when CABG is performed) has undoubtful merits.
In view of extensively used revascularization procedures despite risk reductions achieved with a modern medical treatment, specifically aspirin, statins, betablockers and abciximab, it seems correct to compare medical treatment with revascularization in specific subsets of patients. Some studies of that kind are underway, although the numbers of patients enrolled are relatively small.

It is thought, that the risk of coronary artery disease (CAD) has been substantially reduced using either medical treatment or revascularization procedures with subsequent risk reduction for hard endpoints in all subsets of the clinical expressions of CAD over time. However, no large-scale trials compared the merits of revascularization in relation to medical therapy with aspirin, betablockers and statins in stable CAD and additional abciximab in medically treated patients with unstable coronary syndromes. Such trials are urgently needed, because revascularization may be hazardous in comparison to medical therapy in specific subsets of patients with stable and unstable CAD. 

Recent trials comparing different strategies for the treatment of CAD were inprecise in reporting base-line characteristics of patients especially with regard to left ventricular function, which is still the most important variable for the risk stratification in all subsets of CAD (stable and unstable).

The risk of cardiac death (CD) and acute myocardial infarction (AMI) in a population of subjects with angiographically documented CAD could be expressed in absolute terms, e.g. death and infarction rates per 1000 patients per year and with statement of left ventricular function and the number of diseased vessels, the degree of vessel obstruction and the site of obstruction in order to allow for appropriate comparison of outcomes among different large-scale randomized trials.

This rule of reporting scientific data was observed mainly in the CASS-registry1. From this study, firm evidence was derived in that CABG is essentially benefical in comparison to medically treated subjects only if

1. impaired left ventricular function or

2. severe angina (class III-IV) in patients with normal left ventricular function was noted at baseline.

Until we do not dispose from large-scale trials comparing medical with revascularization therapy, we may use surrogate control groups derived from historical trials having looked at the natural outcome of patients with different expressions of CAD in order to place the merits of revascularization in perspective.

1a. Stable coronary syndromes.
Figures: fibrous plaque with small lipid core: low risk for rupture (=acute coronary syndrome) despite high degree reduction of luminal area.
nollpla3.tif (340660 Byte) nollpla1.tif (340660 Byte)
The control group (DUKE registry): Absolute death rates for medically treated patients with significant coronary narrowing (>75%) and normal or near normal left ventricular function (ejection fraction >50%) during a five year follow-up period15 were 18% for single vessel CAD (1VD, N=307), 28% for 2VD (N=309), 46% for 3VD (N=521) and 39% for 2+3VD (multi vessel disease, MVD, N=830 with 62% of patients having 3 VD). The annual incidence for CD was 12/1000/year in 1 VD, 20/1000/year in 2 VD, 48/1000/year in 3 VD and the corresponding numbers for AMI were 24, 36 and 44 respectively with corresponding numbers for the combined risk for CD and AMI of 36, 56 and 92 respectively (table 1). The CD rate was 38/1000/year for MVD. The corresponding number for AMI rate was 40, the combined number (CD and AMI rates) was 78/1000/year15. Of note, the overall CD rate of 38/1000/y in the DUKE registry was quite comparable to the CD rate of 34/1000/year reported in the CASS registry1, a number taken from the observational arm of medically treated patients with follow-up of 5 years and having MVD (N=930, 71% of patients having 3 VD).
Table 1: The natural course of CAD, Duke registry15

CD: denotes cardiac death. AMI: denotes acute myocardial infarction. VD: denotes vessel disease

The DUKE registry numbers were derived from patients who did not take aspirin or statins. Aspirin may reduce cardiac death rates by 3/1000 treated patients4 , statins by 7/1000 treated patients3 with an expected overall effect in absolute risk reduction of CD rates of about 10/1000 treated patients. Corresponding numbers for the risk reduction of developing non-fatal AMI are 7/1000/year for aspirin4 and 14/1000/year for statins3.

Implementing these numbers in the 5 year follow-up DUKE medically treated patient registry15 with MVD e.g. we would expect an anually CD rate of 28/1000 and an AMI rate of 19/1000 in medically treated patients and an absolute risk for CD and AMI rates of 47/1000/year instead of 78/1000/year. Such numbers could serve as a reference to which any type of intervention in patients with CAD, normal or near normal left ventricular function at rest and stable coronary disease could be compared with.

CABG versus PTCA Large scale randomized trials have been reported in the past few years addressing the question, whether CABG offers advantages in comparison to PTCA in terms of risk reduction for hard end points in patients with multivessel disease2,11,12 and found no difference for hard event outcomes in patients with multi-vessel CAD except for a strong favorisation of CABG over PTCA in patients using anti-diabetic medication11. None of these studies reported the absolute death and AMI rates in relation to the number of diseased vessels and impaired left ventricular function precisely. Moreover, there is no large scale randomized trial comparing medical therapy with revascularization in patients with normal left ventricular function. Importantly, patients who refused to be randomized to revascularization had a statistically better outcome for cardiac death rates than their revascularized counterparts11.
Medical group (DUKE registry 1969-78) versus CABG or PTCA











The CD and AMI rates for patients with MVD and normal or near normal left ventricular function can be derived from the recently reported CABG versus PTCA treatment trials having included a total of 2285 patients during a follow- up time of slightly more than one year2,11,12. In these trials, CD rates of revascularized patients with MVD was 15/1000/ year, AMI rate 31/1000/year and combined rates of CD and AMI 46/1000/year. Thus, in comparison to the reference group taken from the DUKE registry, revascularization can be expected to reduce CD rates by about 23/1000/year and AMI rates by 9/1000/year. It must be emphasized however, that about 65% of medically treated patients had 3 VD in the DUKE registry, whereas 3 VD was present in only about 40% of patients randomized in the ERACI and EAST trial (percent of patients with 3VD are not available from the published report of the BARI trial) and that none of the patients from the DUKE registry had a medical therapy with aspirin and statins.

A compilation of the effect of CABG in randomized trials compared to medical therapy was published in the Lancet in 19946. In these 2649 observationally studied patients the medically treated patients had significantly lower event rates for the combined outcome of CD and AMI (80/1000 vs 116/1000, p<0.001) at the follow-up of one year. At a 5 year follow-up, the overall AMI rate was identical for CABG and medically treated patients (28,4/1000 vs 29,8/1000) whereas cardiac mortality was significantly lower in CABG patients having saved 12 lives in 1000 treated patients during a follow-up period of one year (20/1000 vs 32/1000). Thus, CABG offered an overall advantage for the reduction of CD but not AMI rates, but thousands of patients had to be treated in order to show a small but statistically significant benefit of revascularization over medical treatment, despite the fact, that most medically treated patients did not take aspirin (about 80%) and no patient took statins.

The EPISTENT trial18 compared 2399 multicenter patients from Canada and the U.S. and showed a dramatic risk reduction with ReoPro of 54% for the combined end point of CD, AMI or need for urgent revascularization at 30 days of follow-up in a population with various expression of CAD, mainly about 35% with UAP (<48 hours) and 16% with AMI (<7 days). The combined end point of hard events at 30 days was defined as 1. cardiac death, 2. non-fatal transmural infarction, and 3. large non-Q wave myocardial infarction (CK elevation >5 times). 4. Small non-Q wave myocardial infarctions (CK elevation 3-5 times) were considered negligible and not included in the main analysis. However, patients with periprocedural small myocardial infarctions have a poor outcome10 and should be treated like acute myocardial infarction (see below: section entitled thrombus). The number of hard endpoints (CD or any size of AMI) at 30 days of follow-up was 102/1000 for revasularized Stent + placebo patients (without ReoPro) and 48/1000 in patients with  Stent + abciximab therapy. Placing these results into perspective with the results reported by Yusuf6, the addition of ReoPro (Abciximab) prevented the hazards due to extensively performed revascularization prodecures with an achievement of comparable outcome in hard end-points among patients treated between 1972 and 1984 with CABG (48/1000/year) or medically (62/1000/year) and keeping in mind that the EPISTENT hard events were derived from an only 30 days follow-up. Furthermore, the excessively high rate of CD and AMI of 102/1000/year in the EPISTENT trial with regard to the Stent + placebo group versus 62/1000/y hard events in the historical medically treated group with 2 or 3 VD (see Table 1) and 88/1000/y of hard events in a large number of patients with UAP treated medically before 1990 (Table 2) raises some concerns about the safety of coronary interventions in patients without the use of ReoPro.

Medical groups versus PTCA








ACIP Trial







Attempts to compare medical therapy with PTCA in randomized trials were rare so far. The  RITA-2 trial adds evidence to the concern about the safety of PTCA in a large-scale randomized trial (N=1018) having included patients with mainly mild coronary artery disease (60% had single vessel CAD) and found a statistically significant excess rate for CD and AMI (6.3% vs 3.3% at 2.7 years of follow-up, p=0.02)46. The medically treated arm of patients in this trial (follow-up 2.7 years) had a hard event rate (CD + non fatal AMI) of 9/1000/y, significantly lower when compared to the patients treated with PTCA (19/1000/y). Thus, although PTCA may offer immediate, but often (40%) not constant symptom relief to coronary patients, it may have a negative impact on their prognosis.

Another landmark study (AVERT-trial) reported in November 1998 at the American Heart Meeting in Dallas, Texas compared the effect of a) high dose Atorvastatin to b) PTCA and usual medical therapy in 341 patients with mainly single vessel disease and normal left ventricular function who were candidates for PTCA and with follow-up of 18 months. The goal of the intensive lipid therapy was to achieve an LDL-level below 2.6 mmol/l. In this study, 87% of the medical group patients remained free of cardiovascular events during follow-up. The percent of cardiovascular events - defined as nonfatal MI, bypass surgery, PTCA, and worsening angina - was 13% in the medical and 21% in the PTCA group (p NS). 

In the ACIP trial50 recently published in Circulation, the two year outcome (cardiac death or non-fatal MI) of patients randomized to either early revascularization or ischemia-guided maximal medical therapy were not statistically significant.From the same investigators comes a recently bublished cost-effective analysis (Am J Cardiol 1999;84:1311-1316):"Our study is the first to compare costs associated with randomly assigned initial treatment strategies for patients with chronic [coronary artery disease]," Dr. Knatterud and colleagues say. "These treatments are routinely used with choices representing personal preferences in the absence of controlled trial data."The team concludes that "...early revascularization with long-term follow-up may prove to be cost-effective while improving quality of life during a patient's more productive years."

In view of the favorable results of these pilot-type trials outlined above (eg, short follow up, small numbers of patients and events), larger and longer definitive prognostic trials are clearly required. To this end, the National Heart Lung Blood Institute is initiating two large scale studies (SOCRATES51, COURAGE52) with intermediate duration of follow up (5-6 years) in 6000 and 3260 patients respectively, where intensive medical therapy is compared with revascularization.

1b. Unstable coronary syndromes

Figures: Lipid rich plaque with large lipid core and thin fibrous cap: high risk of rupture (=acute coronary syndrome) despite insignifcant (<50%) degree reduction of luminal area..
nollpla4.tif (340660 Byte) nollpla2.tif (340660 Byte)
White clot versus red clot: 

Patients with unstable angina pectoris (UAP) class III (Braunwald classification) have frequently white clot thrombus (platelet rich thrombus), which can normally not be dissolved by fibrinolytic agents used to dissolve red thrombus, which is very frequent in patients with transmural AMI21. Developement of UAP on the base of disrupted lipid-rich plaques leads to aggregation of thrombocytes or to white clot thrombosis with subsequent increase in vasomotor tone (vasospasm) due to a release of serotonin and thromboxane A222. Thus UAP and possibly non-Q AMI represent a white clot problem, which can be managed by medical therapy using aspirin, heparin, betablockers and glycoprotein IIb/IIIa inhibitors like abciximab or tirofiban and statins, with a risk reduction of any cardiac event at 3 months by about 50% as shown previously for the combined use of aspirin and heparin 23 and recently by an additional risk reductin of 27% when tirofiban is added to a conventional aspirin and heparin treatment with 8.7 deaths or myocardial infarctions at 30 days and 12.3 deaths or myocardial infarctions at 6 months for the active treatment with tirofiban, aspirin and heparin45.

From patients with acute coronary syndromes it is known, that the culprit lesion after successful thrombolysis is usually not severe (mean value 56%30,47) what further underlines the evidence that UAP and acute myocardial infarction is a clot and unstable plaque problem on the top of a usually not severe coronary narrowing. A very exciting albeit small study, the recently published TIMI 14 Trial in Circulation 54 has shown, that combining accelerated TPA with abciximab resulted in a TIMI 3 flow in 76% of patients at 90 minutes, a results that is perfectly comparable to results previously reported for early revascularisation and that this combination of thrombo- and fibrinolysis resolves coronary thrombus on top of mainly non-obstructive leasons.

ReoPro in unstable angina:

Although recently used Abciximab (ReoPro) in unstable coronary syndromes in patients revascularized with PTCA or Stent24,25,26 reduces the risk of in hospital CD, AMI and urgent revascularization rates, these rates remain high (about 65/1000/6 months CD+AMI with and about 130/1000/6 months without RePro in the EPIC24 and EPILOG25 trial) and have not been tested in randomized trials against a medical strategy using aspirin, heparin, abciximab, statins and risk stratification with perfusion myocardial scintigraphy in medically stabilized patients. ReoPro in unstable angina: Although recently used Abciximab (ReoPro) in unstable coronary syndromes in patients revascularized with PTCA or Stent24,25,26 reduces the risk of in hospital CD, AMI and urgent revascularization rates, these rates remain high (about 65/1000/6 months CD+AMI with and about 130/1000/6 months without RePro in the EPIC24 and EPILOG25 trial) and have not been tested in randomized trials against a medical strategy using aspirin, heparin, abciximab, statins and risk stratification with perfusion myocardial scintigraphy in medically stabilized patients.

From studies having collected data in patients studied between 1980-88, where both aspirin and revascularization were used far less frequently than today, we can derive a „natural course„ group from 4 studies31,32, 33,34 having treated 1722 patients for UAP with an overall CD+AMI rate of 88/1000/year (table 2). Moreover, this comparison shows an excess risk for patients with UAP treated with revascularization before the use of ReoPro when compared to medically treated patients (130/1000/6 months versus 88/1000/year) which rises serious concerns about the use of revascularization in UAP, an argument that underlines the importance of the idea, that broadly used revascularization procedures should be compared in randomized trials with medical therapy in specific subsets of patients with CAD.

Hirudin in unstable aninga


The OASIS studies reported at the ESC-meeting in Vienna 1998: More evidence, about what a conservative approach can do in patients treated for UAP comes from the OASIS trials (combined data from the OASIS pilot study and the large OASIS II study), which was reported by Salim Yusuf. In these trials having compared the potential benefits of the specific thrombin inhibitor hirudin vs heparin in 11049 patients with UAP, 6% of patients had early refractory angina during medical therapy and only a total of 7% of patients had to undergo early revascularization (< 7 days from the onset of symptoms). Despite this very low rate of coronary interventions, the 30 day combined endpoint for CD and AMI was 73/1000 (68/1000 in patients randomized to hirudin). These patients, however, were not treated with GPIIa/IIIb inhibitors and compare well with the outcome in patients treated with ReoPro in the EPIC24 and EPILOG25 trials. Since it is known, that beyond 4-8 weeks after the onset of UAP CD and AMI do rarely occur, we can expect that the follow up data (e.g. 6 months) of these patients in the OASIS studies will not be changed substantially.
The PURSUIT trial Another very important and large scale study in the context of nonQ-wave instable coronary syndromes was reported in the New England Journal of Medicine recently49 comparing eptifibatide (a GP IIb/IIIa inhibitor) to placebo in 9461 patients recruited in the US, in Latin American and in Western and Eastern Europe. This trial showed many interesting results with regard to different baseline characteristics of patients  and use of revascularization. with respect to the different regions. Subgroup analyses with respect to outcome and cost efficiency are currently underway. However, preliminary data from the US New England and the British cohort (both traditionally using invasive strategies much less frequently than most remainders) showed these regions to be most effective in terms of costs per live saved.
Table 2:

CD: denotes cardiac death. AMI: denotes acute myocardial infarction. N: denotes numbers of patients

Caveat from the VANQWISH trial This view is underscored by the result of the VANQWISH trial which found a significantly higher death rate in patients with early invasive strategy in nonQ-AMI as compared to a conservative strategy17 at one year of follow-up (N=920: CD 49 in conservative versus 61 in invasive strategy group, non fatal AMI 26 versus 36). It must be emphasized however, that most adverse outcomes int the invasive strategy group were due to high event rates in patients treated with CABG (11%) and not with PTCA (0%). Interestingly, in the invasive group, which did not undergo non-invasive risk assessment N=442), the one-year CD and AMI were highest in the subgroup not having undergone revascularization (N=204 vs 238, CD 31 vs 21 and AMI 25 vs 11) which may be explained by the failure of coronary angiography to risk stratify patients correctly based on plaque morphology only. It will be left to the future analysis, what will be the exact impact of the VANQWISH trial on medical practice. Caveat from the VANQWISH trial: This view is underscored by the result of the VANQWISH trial which found a significantly higher death rate in patients with early invasive strategy in nonQ-AMI as compared to a conservative strategy17 at one year of follow-up (N=920: CD 49 in conservative versus 61 in invasive strategy group, non fatal AMI 26 versus 36). It must be emphasized however, that most adverse outcomes int the invasive strategy group were due to high event rates in patients treated with CABG (11%) and not with PTCA (0%). Interestingly, in the invasive group, which did not undergo non-invasive risk assessment N=442), the one-year CD and AMI were highest in the subgroup not having undergone revascularization (N=204 vs 238, CD 31 vs 21 and AMI 25 vs 11) which may be explained by the failure of coronary angiography to risk stratify patients correctly based on plaque morphology only. It will be left to the future analysis, what will be the exact impact of the VANQWISH trial on medical practice.
DANAMI study

These results are supported by the 49, where a strategy comparing revascularisation of AMI patients (N=1008) with documented ischemia (ST-segment depression during exercise) had statistically significant lower event rates (reinfarction 5.6% vs 10.5%) if revascularized in comparison to patients with post-infarct ischemia and a conservative strategy. In contrast to the VANQWISH trial however, this study did not allow to assess the benefit from non-invasive testing to detect patients who most likely may benefit from revascularization (=those with ischemia !).

Another small but provocative pilot study53 examined the effect of intensive medical therapy compared with coronary angioplasty, both directed at suppressing ischemia in survivors of myocardial infarction. Each patient had large perfusion defects on Thallium scintigraphy which was reduced similarly in both treatment groups and with comparable event rates during follow-up

Thus, this evidence prompts the argument that risk reduction of CD and AMI rates using revascularization procedures may not reach statistically relevant proportions in future studies comparing the outcome especially in patients under optimal medical therapy even if MVD is present. In view of the relatively high number of hard event rates reported even in the most recent trials using PTCA, Stent implantation and ReoPro18, it seems reasonable to argue, that the time for testing lipid lowering and aspirin and ReoPro versus revascularization has come.
GUSTO IV was presented at ESC, Amsterdam 2000

GUSTO stands for "GLOBAL USE OF STRATEGIES TO OPEN OCCLUDED ARTERIES IN ACUTE CORONARY SYNDROMES". In this large trial having included 7800 patients with unstable angina and nonq-wave myocardial infarctions not deemed eligible for percutaneouy interventions, the hypothesis was tested, that adding the potent platelet inhibitor ABCIXIMAB on top of aspirin, heparin and betablockers would reduce hard end points at 30 days, however it did not. The authors expected an event rate for acute MI and cardiac death of 11% at 30 days, but observed only 8% events irrespective of Abciximab. The reasons for this unsuspected findings will not be clarified, until the definitive results will be published. 

Trials in favour of aggressive early strategies in unstable coronary syndromes


A more aggressive approach is generally accepted in high risk patients not responding to medical therapy, exemplified in the TIMI IIIb database substudy of patients not responding to medical therapy, mainly patients with ongoing chest pain, ST-depression, and older age55 .

Just recently, the FRISC II study involving 2457 patients with UAP oder non Q AMI was presented in the Lancet in 199956 6 and has shown an impressive risk reduction in favour of early invasive revascularization versus initial ischemia guided therapy. After a follow up of 6 months the risk for death and non fatal AMI was 9,4% in the invasive versus 12,1% in the medical treatment arm (p=0.031).  

1. Why was the risk of death and non fatal AMI higher for medically treated patients when compared to previous studies (see Table 2 !)? 

2. Why was the risk of primary end points not reduced in women ?  

3. At least 10% of patients in the invasive arm received ReoPro outside of the study protocol, which was not the case in the conservative arm. 

4. Around 25% of patients had previous myocardial infarction. In these patients, risk stratification based on ECG stress tests is often hampered by baseline changes in the rest ECG. Moreover, the cutoff value for exercise induced ischemia was set at a > 3 mm ST depression cut off point (!). 

5. Here a closer look at FRISC II in comparison to VANQWISH: The conservative arm of Vanqwish (N=458) and the conservative arm ofFRISC II (N=1235) may be compared: Age 62 vs 65 almost identical, men  97% vs 68%, revascularisation after 30 days 33% vs 22%, revascularisation after 6 months 38%(?) vs 39%, CD and AMI after 1 year (Vanqwish) in  97% of men 10.7%, after  6 months (FRISC II) only in men 13.9% (women had a better outcome with respect to CD and AMI in the conservative vs invasive strategy (8.3% vs 10.5% !!!). Indication for switch to invasive arm: pathological Thallium scan (Vanqwish), ST-depresssion over 3.0 mm (sic !!!) in FRISC II. In other words: in FRISC II the male patients in the conservative arm were revascularized too late because of too tough ischemia criteria. Moreover: in patients randomized to Dalteparin, there was no significant difference in outcome for the combined endpoint of CD+AMI in the conservative and invasive arm of that study.

In a study published in the NEJM in the first issue of November 1999 a rather small number of patients were randomized either to primary PTCA (N=194) or Streptokinase (N=201) in the setting of acute myocardial infarction. In the short as well as in the long term (5 years) these Dutch authors observed a significantly and sustained better outcome with regard to cardiac death and non fatal AMI in the patients treated with early PTCA57.

diagnostic and prognostic problems inherent to coronary angiography From the angiographer point of view, stenosis >70% are functionally relevant, whereas stenosis of 50(60)-70% are probably functionally relevant. The correct interpretation of coronary stenosis is hampered for several reasons: a) collateral and functionally relevant subepicardial coronary flow cannot be reliably assessed by CA, b) epi-stenotic thrombus is frequently not diagnosed by CA, c) the degree of stenosis is increased during physical exercise, and d) the degree of stenosis is a rather poor predictor for subsequent cardiac events
a) Collaterals:  Collateral flow may be assessed by CA. In one study, visible epicardial flow by CA in patients with acute anterior myocardial infarction was associated with in-hospital death rates of 8% with   versus 23% in patients without angiographyically visible collateral flow respectively14. Subepicardial collateral flow is not visible with routine CA or if visible, not always functionally relevant and may yield completely cardioprotective dimensions when assessed by myocardial contrast echocardiography during acute coronary occlusion with PTCA13. Thus, oculo-stenotic reflexes may lead to revascularization of angiographically relevant but functionally irrelevant coronary artery stenosis. 
b) Thrombus: Intracoronary thrombus is frequently present in patients with CAD (e.g. in 69% in patients with recent AMI, 54% in unstable angina and 29% in stable angina) 16. The sensitivity to detect intracoronary thrombus by CA is 65% and the negative predictive value is 58%16. In patients with intracoronary thrombus, revascularization using PTCA, especially stent-implantation, was defined as the worst ennemy of the interventional cardiologist and is strongly underestimated by coronary angiography16. Relevant CK-elevations (> 3 times normal) occur in up to 15% of patients having undergone PTCA, should be treated as myocardial infarction (irrespective of ECG-findings) and have a poor prognostic outcome, like acute myocardial infarctions10. The in-hospital death, AMI and emergency CABG rate was 14% in patients with and 2% in patients without intracoronary thrombus having undergone revascularization with PTCA20, where 50 (68%) out of 74 thrombi detected by angioscopy where missed by angiography. 
c) Degree of stenosis:



intracoronary pressure estimations

Coronary vasomotor tone has been recognized to play a crucial role in determining the ischemic threshold and the occurence of spontaneous and exercise-induced myocardial ischemia9. Normal coronary vessels show exercise-induced dilation (+14% lumen diameter) which is further enhanced after sublingual nitroglycerin (+32% lumen diameter). In contrast, stenosis show exercise-induced vasoconstriction (-28% lumen diameter), which is partially reversed after sublingual nitroglycerin (+8% lumen diameter). Importantly, there is a significant, inverse correlation between the number of cardiovascular risk factors and mean exercise-induced percent change in coronary luminal area. Newly introduced intracoronary pressure gradient estimations are costly (around 1000 US $ per catheter) and reflect the degree of stenosis after maximal coronary dilatation with nitroglycerin; thus, this method may not be suited to identify the culprit lesion responsible for patients symptoms during physical acitivity. 
bulletMore about fractional flow reserve and the prognostic impact of endothelial function
bulletMore about intravascular ultrasound as a guide for revascularization
bulletDiscussion of the Issue: FFR and IVUS
d) Prediction of coronary events:  traditionally, the more severe a stenosis is found at the time of CA, the higher is the subsequent risk for CD and AMI, thus sealing high grade plaques with PTCA is thought to stabilize the plaque and helps to avoid future cardiac events. The idea of plaque sealing has, to my knowledge, not specifically been tested in clinical trials. 
bulletThe risk for subsequent CD and AMI can be assessed by left ventricular function studies, by the extent score (number of vessels exhibiting a 5 to 75% stenosis in a 15 segment model of the coronary tree), by the number of coronary vessels with stenosis > 75% (e.g. Gensini and Friesinger score=stenosis score), by nuclear imaging and by stress-echocardiography. Comparing left ventricular function, the extent score and the stenosis score in 312 patients with follow-up over a mean period of 3.4 years, Moise35 found (using Cox multivariate analysis) that left ventricular function was the best predictor for CD (chi-square 17.78), followed by the extent score (chi-square 9.87) and the stenosis score (chi-square 6.61). The only statistically relevant predictors of the combinded endpoints (CD, AMI and unstable angina) were left ventricular function (chi-square 12.02) and the extent score (chi-square 8.12), whereas the stenosis score was statistically not significant in this historical population with known CAD and without aspirin and statin medication. Thus, it is the number of minimal to moderate plaques found in the coronary tree that more precisely defines the patients risk for subsequent cardiac hard-point events more than the presence of severe coronary obstruction. Of note, left ventricular function was found to be the best predictor for subsequent cardiac events, over coronary anatomy.

In another study38, 17 patients with AMI were identified with previous coronary angiograms. Only in 4 patients, the previous stenosis was found to have a degree of obstruction > 70%.


The location of future AMI was correctly predicted by SestaMIBI myocardial perfusion imaging in 63% of patients37a and by stress-echocardiography in 46%37b.


The modern pathophysiological concept explaining these findings has been described extensively elsewhere36. In brief (see figures above), mainly lipid-rich (unstable) plaques may cause disruption or thrombus formation on the base of intimal erosion with subsequently increased risk for CD, AMI and unstable angina. These plaques are rarely obstructive but may appear obstructive by thrombus formation on coronary angiography.


From these observational studies we are confronted with the counterintuitive and remarkable conclusions, that CA does not accurately predict the site of future coronary events, that plaque sealing most often is performed in sites where future cardiac events may not occur and that aspirin and statins appear as a valuable, low-cost and scientifically approved means for plaque sealing (stabilization) in the whole coronary tree.


In view of the potential hazards of plaque sealing of coronary vessels without documented ischemia, the concept of plaque sealing should be abandoned except for high risk stenosis (proximal > 90% stenosis in two of the main coronary vessels). Plaque sealing is so far just an idea, which was never tested in randomized trials.


PTCA did not significantly reduce CD rates in comparison with medical therapy for any subset of severity of CAD reported from an observational trial including 3557 patients with medical therapy and 2626 patients having undergone PTCA39 during a follow-up time of 5 years.


Finally, myocardial perfusion scintigraphy has been shown to yield incremental information with regard to cardiac prognosis over clinical and coronary angiographic data44.

3. Modern non-invasive testing 

Cedars Sinai Medical Center: great experience with myocardial perfusion imaging

From a clinical point of view, we need to know, which patients may benefit from revascularization and in which patients we can safely avoid coronary angiography. Because of the importance of this issue for public health, only large scale trials should be addressed to answer this question.

As recently published in Circulation8, 5183 patients followed up for a mean of 642 days and assessed by myocardial perfusion scintigraphy, showed a death rate of 3/1000/year and an AMI rate of 5/1000/year in normal scans (combined 9/1000/year) and a death death rate of 8/1000/year and an AMI rate of 27/1000/year in mildly abnormal scintigraphic scans (combined CD+AMI rates of 35/1000/year). From this large-scale trial, we can argue with keeping mortality and AMI rates reported from recently published revascularization trials in mind, that no revascularization modality may reduce cardiac risk in this low-risk population. Similar results were published recently for the stress-echocardiography with dobutamine and atropine48. Moreover, the Hachamovich study adds important scientific information to the concept of risk reduction by ischmia guided therapy.

Similar efficacy (negative predictive values >90%) in risk assessment using non-invasive testing has been reported in patients with unstable coronary syndromes27,28,29.

The concept of performing CA only in patients with persistent coronary symptoms despite medical therapy, in patients with relevant ischemia as assessed by non-invasive testing or in patients with relevant reductions of left ventricular function (e.g. EF<30%) is in agreement with the official guidelines of the European Society of Cardiology40,42 having been published for the management of stable angina pectoris and acute myocardial infarction. Moreover, there is a perception of coronary intervention overuse also in patients post AMI, as pointed out recently in an editorial in the European Journal of Cardiology28.


Clinical assessment, exercise testing, myocardial perfusion scintigraphy and stress echocardiography offer important clues to the risk management of patients with suspected or proven coronary artery disease presenting with stable and unstable coronary syndromes and should be used extensively to identify patients with low risk for subsequent cardiac death and myocardial infarction in order to avoid potentially hazardous revascularizations of „dangerous" coronary artery stenoses as defined by coronary angiography.


Although several caveats are known to the medical community inherent to the invasive approach of CAD treatment, and keeping in mind the high efficacy of stabilizing patients in terms of subsequent risk of cardiac death and acute myocardial infarction using medical treatment and the „help" of non-invasive risk stratification strategies, the time to test the outcome of CAD patients in large-scale studies comparing invasive versus medical strategies addressing mainly patients with normal or near normal left ventricular function, which is the most powerful discriminator for subsequent cardiac risk, has come.


The data reported in this review place the enthusiasm of invasively acting cardiologists treating patients with various clinical expressions of coronary artery disease in perspective and furnishes arguments to a maximal medical, yet conservative approach in the management of patients with acceptable cardiac risk as assessed by clinical evaluation and non-invasive testing.


It must be emphasized, however, that the recent progress in term of risk reduction achieved by invasive strategies using the adjuncts  of GPIIa/IIIb inhibitors and Stent implantation is dramatic (up to - 50%). Nevertheless, it must be proven in the future, that these strategies do not only offset   the harm of too extensively used revascularization as performed recently (not having used these adjuncts) and remain cost efficient and prognostically relevant in comparison to an aggressive, yet conservative approach offered to patients suffering from acute and chronic coronary syndromes.


Most opinion leaders, even when acting as interventional cardiologists, are clearly supporting  these conclusions and await future randomized trials comparing medical vs invasive therapeutic stratagies in coronary artery disease. In the short come, we expect stenting and the use of GP IIb/IIIa receptor blockers to have an overwhelming use. Awaiting trials in the farer future, the question is: " Non-invasive therapy might be better. How soon will this be finally proven ?".

Comment: this review is a subject of continuous reevaluation furnished by newer scientific reports, has not been published anywhere, is not peer reviewed and is meant as a paper open for debate.


Please klick here to send a message: info@kardiolab.ch


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Abstracts and Internet files:

ARTICLE TITLE: Influence of collateral circulation on in-hospital death from anterior acute myocardial infarction.

ARTICLE SOURCE: J Am Coll Cardiol (United States), Mar 1 1998, 31(3) p512-8

AUTHOR(S): Perez-Castellano N; Garcia EJ; Abeytua M; Soriano J; Serrano JA; Elizaga J; Botas J; Lopez-Sendon JL; Delcan JL

ABSTRACT: OBJECTIVES: Our purpose was to study whether the in-hospital prognosis of anterior acute myocardial infarction (AMI) is influenced by preexistent collateral circulation to the infarct-related artery. BACKGROUND: Collateral circulation exerts beneficial influences on the clinical course after AMI, but demonstration of improved survival is lacking. METHODS: We studied 238 consecutive patients with anterior AMI treated by primary angioplasty within the first 6 h of the onset of symptoms. Fifty-eight patients with basal Thrombolysis in Myocardial Infarction (TIMI) flow 1 in the infarct-related artery or with inadequate documentation of collateral circulation were excluded. Collateral channels to the infarct-related artery before angioplasty were angiographically assessed, establishing two groups: 115 patients (64%) without collateral vessels (group A) and 65 patients (36%) with collateral vessels (group B). RESULTS: There were no differences in baseline characteristics between groups A and B, except for the greater prevalence of previous angina in group B (15% vs. 34%, p = 0.003). During the hospital stay, 26 patients (23%) in group A and 5 (8%) in group B died (p = 0.01). Cardiogenic shock accounted for 74% of deaths. Cardiogenic shock developed in 30 patients (26%) in group A and in 4 (6%) in group B (p = 0.001). The absence of collateral circulation appeared to be an independent predictor of in-hospital death (odds ratio 3.4, 95% confidence interval 1.2 to 9.6, p = 0.02) and cardiogenic shock (odds ratio 5.6, 95% confidence interval 1.9 to 17, p = 0.002). CONCLUSIONS: Preexistent collateral circulation decreases in-hospital death from anterior AMI by reducing the incidence of cardiogenic shock.

ARTICLE TITLE: Coronary thrombi increase PTCA risk. Angioscopy as a clinical tool.

ARTICLE SOURCE: Circulation (United States), Jan 15 1996, 93(2) p253-8

AUTHOR(S): White CJ; Ramee SR; Collins TJ; Escobar AE; Karsan A; Shaw D; Jain SP; Bass TA; Heuser RR; Teirstein PS; Bonan R; Walter PD; Smalling RW

ABSTRACT: BACKGROUND: The presence of angiographically identified intracoronary thrombus has been variably associated with complications after coronary angioplasty. Angiography has been shown to be less sensitive than angioscopy for detecting subtle details of intracoronary morphology, such as intracoronary thrombi. The clinical importance of thrombi detectable by angioscopy but not by angiography is not known. METHODS AND RESULTS: Percutaneous coronary angioscopy was performed in 122 patients undergoing conventional coronary balloon angioplasty (PTCA) at six medical centers. Unstable angina was present in 95 patients (78%) and stable angina in 27 (22%). Therapy was not guided by angioscopic findings, and no patient received thrombolytic therapy as an adjunct to angioplasty. Coronary thrombi were identified in 74 target lesions (61%) by angioscopy versus only 24 (20%) by angiography. A major in-hospital complication (death, myocardial infarction, or emergency bypass surgery) occurred in 10 of 74 patients (14%) with angioscopic intracoronary thrombus, compared with only 1 of 48 patients (2%) without thrombi (P = .03). In-hospital recurrent ischemia (recurrent angina, repeat PTCA, or abrupt occlusion) occurred in 19 of 74 patients (26%) with angioscopic intracoronary thrombi versus only 5 of 48 (10%) without thrombi (P = .03). Relative risk analysis demonstrated that angioscopic thrombus was strongly associated with adverse outcomes (either a major complication or a recurrent ischemic event) after PTCA (relative risk, 3.11; 95% CI, 1.28 to 7.60; P = .01) and that angiographic thrombi were not associated with these complications (relative risk, 0.85; 95% CI, 0.36 to 2.00; P = .91). CONCLUSIONS: The presence of intracoronary thrombus associated with coronary stenoses is significantly underestimated by angiography. Angioscopic intracoronary thrombi, the majority of which were not detected by angiography, are associated with an increased incidence of adverse outcomes after coronary angioplasty.

ARTICLE TITLE: Clinical and angiographic implications of coronary stenting in thrombus-containing lesions.

ARTICLE SOURCE: J Am Coll Cardiol (United States), Mar 15 1997, 29(4) p725-33

AUTHOR(S): Alfonso F; Rodriguez P; Phillips P; Goicolea J; Hernandez R; Perez-Vizcayno MJ; Fernandez-Ortiz A; Segovia J; Banuelos C; Aragoncillo P; Macaya C

ABSTRACT: OBJECTIVES: This study sought to determine the results of coronary stenting in thrombus-laden lesions. BACKGROUND: The angiographic evidence of intracoronary thrombus has classically been considered a formal contraindication to stent implantation. However, with increasing use of stenting, the indications for this technique have widened to include treatment of patients who have an acute coronary syndrome or lesions with adverse anatomic features. METHODS: We studied 86 consecutive patients (mean age +/- SD 61 +/- 11 years, 14 women) undergoing coronary stenting of a thrombus-containing lesion; the procedure was performed electively in 39% and after angioplasty failure in 61%. Sixty-four patients (75%) were treated for unstable angina, and 19 (22%) underwent the procedure during an acute myocardial infarction. A specific protocol that included clinical and late angiographic follow-up was used. RESULTS: Angiographic success was obtained in 83 patients (96%). Five patients (6%) died during the hospital stay despite angiographic success; four of these had cardiogenic shock, and one (1%) had subacute stent thrombosis. Non-Q wave myocardial infarction developed in five additional patients (6%), and four of these five had data consistent with distal embolization. Of the 78 patients discharged with angiographic success, 67 (86%) were event-free and clinically improved at last follow-up visit (12 +/- 11 months). During the follow-up period, eight patients required repeat angioplasty, one patient required heart transplantation, and two patients died. Quantitative angiography demonstrated excellent angiographic results after stenting (minimal lumen diameter 0.31 +/- 0.4 vs. 2.77 +/- 0.6 mm). Late angiographic follow-up (5.5 +/- 1 months) was obtained in 50 patients with 54 lesions (93% of eligible), revealing a minimal lumen diameter of 2.0 +/- 1 mm and restenosis (lumen narrowing 50%) in 18 lesions (33%). CONCLUSIONS: Coronary stenting constitutes an effective therapeutic strategy for patients with thrombus-containing lesions, either after failure of initial angioplasty or electively as the primary procedure. Coronary stenting in this adverse anatomic setting results in a high degree of angiographic success, a low incidence of subacute thrombosis and an acceptable restenosis rate.

ARTICLE TITLE: Evidence for prevention of death and myocardial infarction with platelet membrane glycoprotein IIb/IIIa receptor blockade by abciximab (c7E3 Fab) among patients with unstable angina undergoing percutaneous coronary revascularization. EPIC Investigators.Evaluation of 7E3 in Preventing Ischemic Complications.

ARTICLE SOURCE: J Am Coll Cardiol (United States), Jul 1997, 30(1) p149-56

AUTHOR(S): Lincoff AM; Califf RM; Anderson KM; Weisman HF; Aguirre FV; Kleiman NS; Harrington RA; Topol EJ

ABSTRACT: OBJECTIVES: We sought to evaluate whether patients with unstable angina undergoing coronary intervention derive particular clinical benefit from potent platelet inhibition. BACKGROUND: Plaque rupture and platelet aggregation are pathogenetic processes common to unstable angina and ischemic complications of percutaneous coronary intervention. METHODS: Of the 2,099 patients undergoing a coronary intervention in the Evaluation of 7E3 in Preventing Ischemic Complications (EPIC) trial, 489 were enrolled with the diagnosis of unstable angina and randomized to receive placebo, an abciximab (c7E3) bolus immediately before the intervention or an abciximab bolus followed by a 12-h infusion. The primary end point was a composite of death, myocardial infarction (MI) or urgent repeat revascularization within 30 days of randomization. The occurrence of death, MI or any revascularization within 6 months was also assessed. RESULTS: Compared with placebo, the bolus and infusion of abciximab resulted in a 62% reduction in the rate of the primary end point (12.8% vs. 4.8%, p = 0.012) among patients with unstable angina, due primarily to a reduction in the incidences of death (3.2% vs. 1.2%, p = 0.164) and MI (9% vs. 1.8%, p = 0.004). By 6 months, cumulative death and MI were further reduced by abciximab (6.6% vs. 1.8%, p = 0.018 and 11.1% vs. 2.4%, p = 0.002, respectively). The magnitude of the risk reduction with abciximab was greater among the patients with unstable angina than among other patients in the EPIC trial without unstable angina for the end points of death (interaction: p = 0.008 at 30 days, p = 0.002 at 6 months) and MI (interaction: p = 0.004 at 30 days, p = 0.003 at 6 months). CONCLUSIONS: The syndrome of unstable angina identifies patients who will experience particularly marked reductions in the risk of death and MI with abciximab during coronary intervention.

ARTICLE TITLE: Angioplasty of complex lesions in ischemic rest angina: results of the Thrombolysis and Angioplasty in Unstable Angina (TAUSA) trial.

ARTICLE SOURCE: J Am Coll Cardiol (United States), Oct 1995, 26(4) p961-6

AUTHOR(S): Mehran R; Ambrose JA; Bongu RM; Almeida OD; Israel DH; Torre S; Sharma SK; Ratner DE

ABSTRACT: OBJECTIVES. This study sought to analyze the role of complex lesion morphology on the acute results of angioplasty. BACKGROUND. Acute complications of angioplasty are higher in unstable than in stable angina. The unstable culprit lesion is usually complex, indicative of plaque disruption and thrombus formation. Previous nonrandomized studies have shown that the presence of intracoronary thombus increases morbidity after coronary angioplasty. The role of complex morphology in coronary angioplasty outcome was studied in a prespecified subgroup analysis of a large multicenter coronary angioplasty trial. METHODS. The results of coronary angioplasty from the Thrombolysis and Angioplasty in Unstable Angina (TAUSA) trial were analyzed. This large trial randomized 469 patients in double-blinded manner to receive either intracoronary urokinase or placebo during coronary angioplasty of the culprit lesion in ischemic rest angina with or without recent infarction. The study presented here analyzes in detail the results of coronary angioplasty in complex versus simple lesions in the urokinase and placebo groups. Complex lesions were defined before angioplasty by a core laboratory as having one or more of the following: irregular borders, overhanging edges, ulcerations or intraluminal filling defects proximal or distal to the lesion. RESULTS. Of the 469 patients, 458 had identifiable culprit lesions, of which 245 were complex and 213 were simple. Complex lesions were associated with a higher abrupt closure rate than simple lesions (10.6% vs. 3.3%, respectively, p 0.003). Patients with complex lesions also had higher recurrent in-hospital angina (p 0.02) and emergent bypass surgery (p 0.02). Further analysis of complex lesions revealed that abrupt closure was particularly high in the urokinase group (15.0% vs 5.9% for the placebo group, p 0.03), and most abrupt closures were thrombotic. Composite clinical end points were also significantly higher with complex lesions and urokinase. In the placebo group, complex lesions had a higher abrupt closure rate as well as postcoronary angioplasty filling defects, but clinical end points were not significantly different. CONCLUSIONS. Complex lesions before coronary angioplasty increase acute complication rates after coronary angioplasty. Urokinase as administered in the TAUSA trial had significant adverse effects, especially in complex lesions. However, even in the placebo arm, complex lesions were associated with higher complication rates than simple lesions. Newer antithrombotic measures that particularly target the platelet may eventually decrease complication rates in these lesions.

ARTICLE TITLE: Increased risk of non-Q wave myocardial infarction after directional atherectomy is platelet dependent: evidence from the EPIC trial. Evaluation of c7E3 for the Prevention of Ischemic Complications.

ARTICLE SOURCE: J Am Coll Cardiol (United States), Oct 1996, 28(4) p849-55

AUTHOR(S): Lefkovits J; Blankenship JC; Anderson KM; Stoner GL; Talley JD; Worley SJ; Weisman HF; Califf RM; Topol EJ

ABSTRACT: OBJECTIVES: We sought to determine the effects of platelet glycoprotein IIb/IIIa receptor blockade on adverse outcomes, especially non-Q wave myocardial infarction, in patients undergoing directional atherectomy in the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial. BACKGROUND: Randomized trials comparing directional atherectomy with percutaneous transluminal coronary angioplasty (PTCA) have demonstrated modest benefits favoring atherectomy but at a cost of increased acute ischemic complications, notably non-Q wave myocardial infarction. The mechanism for this excess risk is unknown. METHODS: Of 2,038 high risk patients undergoing coronary intervention in the EPIC trial, directional atherectomy was performed in 197 (10%). Patients randomly received the chimeric glycoprotein IIb/IIIa antibody 7E3 (c7E3), as a bolus or a bolus and 12-h infusion or placebo. Study end points included death, myocardial infarction, repeat intervention or bypass surgery. RESULTS: Patients undergoing directional atherectomy had a lower baseline risk for acute complications but had a higher incidence of any myocardial infarction (10.7% vs. 6.3%, p = 0.021) and non-Q wave myocardial infarction (9.6% vs. 4.9%, p = 0.006). Bolus and infusion of c7E3 reduced non-Q wave myocardial infarctions by 71% after atherectomy (15.4% for placebo vs. 4.5% for bolus and infusion, p = 0.046). Non-Q wave myocardial infarction rates after PTCA were not affected by c7E3, although Q wave myocardial infarctions were reduced from 2.6% to 0.8% (p = 0.017). CONCLUSIONS: The EPIC trial confirmed the increased risk of non-Q wave myocardial infarction with directional atherectomy use compared with PTCA. A bolus and 12-h infusion of the glycoprotein IIb/IIIa receptor inhibitor c7E3 abolished this excess risk. Directional atherectomy-related non-Q wave myocardial infarction appears to be platelet aggregation dependent.

ARTICLE TITLE: An overview of the results of the EPIC trial.

ARTICLE SOURCE: Eur Heart J (England), Nov 1995, 16 Suppl L p43-9

AUTHOR(S): Califf RM; Lincoff AM; Tcheng JE; Topol EJ

ABSTRACT: The Evaluation of 7E3 for the Prevention of Ischaemic Complications (EPIC) trial assessed the use of abciximab in the treatment of patients at high risk undergoing percutaneous revascularization procedures. Abciximab (c7E3) is a chimeric monoclonal antibody targeted to block the glycoprotein IIb/IIIa receptor on the surface of the platelet; this receptor is believed to be the final common pathway of platelet aggregation. Administered at the time of angioplasty or directional coronary atherectomy, abciximab had a beneficial effect in the population studied, which included patients considered to be at high risk from complications of the procedure, based on the presence of acute or recent myocardial infarction, severe unstable angina or adverse coronary morphological characteristics. Abciximab reduced the risk of the primary endpoint at 30 days (death, myocardial infarction, repeat angioplasty or bypass surgery for recurrent ischaemia, balloon pump or stent insertion for ischaemia) by 35%: from 12.8% in the placebo group to 8.3% in patients treated with abciximab bolus and infusion. This trend was observed as a whole and in each component of the primary endpoint. At 6 months follow-up, the effect of the treatment was modestly enhanced beyond 30 days. A variety of substudies have documented substantial evidence of treatment benefit in patients with acute myocardial infarction and unstable angina. Non-fatal infarction, observed as beyond that normally expected in other studies with directional coronary atherectomy, was not above normal in patients treated with abciximab, and there was evidence of a treatment benefit in the elderly, although more information would be helpful in patients over the age of 70. The substantial site-to-site variability indicates that standardization of percutaneous revascularization could enhance the benefit of abciximab, while reducing bleeding complications.

ARTICLE TITLE: Stress echocardiographic results predict risk of reinfarction early after uncomplicated acute myocardial infarction: large-scale multicenter study. Echo Persantine International Cooperative (EPIC) Study Group.

ARTICLE SOURCE: J Am Coll Cardiol (United States), Oct 1995, 26(4) p908-13

AUTHOR(S): Picano E; Pingitore A; Sicari R; Minardi G; Gandolfo N; Seveso G; Chiarella F; Bolognese L; Chiaranda G; Sclavo MG; et al

ABSTRACT: OBJECTIVES. This study sought to assess the value of dipyridamole echocardiography in predicting reinfarction in patients evaluated early after uncomplicated acute myocardial infarction. BACKGROUND. The identification of future nonfatal reinfarction seems an elusive target for physiologic testing. However, a large sample population is needed to detect minor differences in phenomena with a low event rate. METHODS. We assessed the value of dipyridamole echocardiography in predicting reinfarction in 1,080 patients (mean [+/- SD] age 56 +/- 9 years; 926 men, 154 women) evaluated early (10 +/- 5 days) after uncomplicated acute myocardial infarction and followed up for 14 +/- 10 months. RESULTS. Submaximal studies due to limiting side effects occurred in 14 patients (1.3%); these test results were included in the analysis. Results of dipyridamole echocardiography were positive in 475 patients (44%). During follow-up, there were 50 reinfarctions: 45 nonfatal, 5 fatal (followed by cardiac death or = 4 days after reinfarction). Reinfarction (either nonfatal or fatal) occurred in 30 patients with positive and 20 with negative results (6.3% vs. 3.3%, p 0.01). Nonfatal reinfarction occurred in 25 patients with positive and 20 with negative results (5% vs. 3.3%, p 0.05). Reinfarction was fatal in 5 of 30 patients with positive and in none of 20 with negative results (16.6% vs. 0%, p = 0.07). The relative risk of reinfarction was 1.9. CONCLUSIONS. Dipyridamole echocardiographic positivity identifies patients evaluated early after uncomplicated acute myocardial infarction at higher risk of reinfarction, especially fatal reinfarction.

ARTICLE TITLE: Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The EPILOG Investigators

ARTICLE SOURCE: N Engl J Med (United States), Jun 12 1997, 336(24) p1689-96

ABSTRACT: BACKGROUND: Blockade of the platelet glycoprotein IIb/IIIa receptor with abciximab (a monoclonal-antibody Fab fragment directed against the receptor) has been shown to diminish ischemic complications among patients undergoing high-risk coronary angioplasty or directional atherectomy but increases bleeding complications. The widespread applicability of this treatment is unknown, particularly in view of the observed risk of hemorrhage. METHODS: In a prospective, double-blind trial, we randomly assigned patients undergoing urgent or elective percutaneous coronary revascularization at 69 centers to receive abciximab with standard-dose, weight-adjusted heparin (initial bolus of 100 U per kilogram of body weight); abciximab with low-dose, weight-adjusted heparin (initial bolus of 70 U per kilogram); or placebo with standard-dose, weight-adjusted heparin. The primary efficacy end point was death from any cause, myocardial infarction, or urgent revascularization within 30 days of randomization. RESULTS: The trial was terminated at the first interim analysis, with 2792 of the planned 4800 patients enrolled. At 30 days, the composite event rate was 11.7 percent in the group assigned to placebo with standard-dose heparin; 5.2 percent in the group assigned to abciximab with low-dose heparin (hazard ratio, 0.43; 95 percent confidence interval, 0.30 to 0.60; P 0.001); and 5.4 percent in the group assigned to abciximab with standard-dose heparin (hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.63; P 0.001). There were no significant differences among the groups in the risk of major bleeding, although minor bleeding was more frequent among patients receiving abciximab with standard-dose heparin. CONCLUSIONS: Inhibition of the platelet glycoprotein IIb/IIIa receptor with abciximab, together with low-dose, weight-adjusted heparin, markedly reduces the risk of acute ischemic complications in patients undergoing percutaneous coronary revascularization, without increasing the risk of hemorrhage.

ARTICLE TITLE: Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study

ARTICLE SOURCE: Lancet (England), May 17 1997, 349(9063) p1429-35

ABSTRACT: BACKGROUND: Platelet aggregation is a dominant feature in the pathophysiology of unstable angina. Percutaneous transluminal coronary angioplasty (PTCA) in patients with this disorder carries an increased risk of thrombotic complications. Abciximab (c7E3) blocks the platelet glycoprotein IIb/IIIa receptor, thus preventing platelet adhesion and aggregation. The CAPTURE study was a randomised placebo-controlled multicentre trial to assess whether abciximab can improve outcome in patients with refractory unstable angina who are undergoing PTCA. METHODS: The study recruited patients with refractory unstable angina, defined as recurrent myocardial ischaemia under medical treatment including heparin and nitrates. Predefined stopping rules were met at a planned interim analysis of data for 1050 patients, and recruitment was stopped. Data for 1265 patients (of 1400 scheduled) are presented here. After angiography, patients received a randomly assigned infusion of abciximab or placebo for 18-24 h before PTCA, continuing until 1 h afterwards. The primary endpoint was the occurrence within 30 days after PTCA of death (any cause), myocardial infarction, or urgent intervention for recurrent ischaemia. Analyses were by intention to treat. FINDINGS: By 30 days, the primary endpoint had occurred in 71 (11.3%) of 630 patients who received abciximab compared with 101 (15.9%) of 635 placebo recipients (p = 0.012). The rate of myocardial infarction was lower in the abciximab than in the placebo group before PTCA (four [0.6%] vs 13 [2.1%], p = 0.029) and during PTCA (16 [2.6%] vs 34 [5.5%], p = 0.009). Major bleeding was infrequent, but occurred more often with abciximab than with placebo (24 [3.8%] vs 12 [1.9%], p = 0.043). At 6-month follow-up, death, myocardial infarction, or repeat intervention had occurred in 193 patients in each group. INTERPRETATION: In patients with refractory unstable angina, treatment with abciximab substantially reduces the rate of thrombotic complications, in particular myocardial infarction, before, during, and after PTCA. There was no evidence that this regimen influenced the rate of myocardial infarction after the first few days, or the need for subsequent reintervention.

ARTICLE TITLE: Intracoronary morphology of culprit lesions after reperfusion in acute myocardial infarction: serial angioscopic observations.

ARTICLE SOURCE: J Am Coll Cardiol (United States), Mar 1 1996, 27(3) p606-10

AUTHOR(S): Ueda Y; Asakura M; Hirayama A; Komamura K; Hori M; Komada K

ABSTRACT: OBJECTIVE: This study sought to elucidate the morphologic and pathologic characteristics of culprit lesions in patients with acute myocardial infarction. BACKGROUND: The pathogenic mechanisms of acute myocardial infarction have been discussed on the basis of postmortem histologic examinations. Disruption of lipid-rich plaques is thought to render them thrombogenic. However, the details of coronary morphology have not been elucidated in survivors of myocardial infarction. The quality of angioscopic images has been greatly improved, and clear visualization of the intracoronary milieu can now be obtained. METHODS: Eleven patients with acute myocardial infarction and angiographic demonstration of the culprit lesion were entered into the study. Angioscopic observations were made immediately after reperfusion and at 1-month follow-up. RESULTS: Angioscopic observations were successfully performed in 10 patients immediately after reperfusion and in 10 at 33 +/- 26 (mean +/- SD) days of follow-up. Immediately after reperfusion, red thrombus, white thrombus, yellow plaques and intimal flaps were recognized in 30% (95% confidence interval [CI] 25.7 to 35.7), 100%, 100% and 50% (95% CI 45.0 to 55.0) of patients, respectively. At follow-up, these were recognized in 10% (95% CI 6.6 to 16.4), 60% (95% CI 54.6 to 64.7), 100% and 40% (95% CI 35.3 to 45.4) of patients, respectively. CONCLUSIONS: The thrombus in acute myocardial infarction was always recognized over the yellow plaques. The thrombus formed directly over the plaque was mainly white. Red thrombus might be formed after the blood flow was obstructed by the white thrombus. At approximately 1 month, yellow plaques remained in all patients, and 50% still had adherent white thrombus.

ARTICLE TITLE: A randomized trial of low osmolar ionic versus nonionic contrast media in patients with myocardial infarction or unstable angina undergoing percutaneous transluminal coronary angioplasty.

ARTICLE SOURCE: J Am Coll Cardiol (United States), May 1996, 27(6) p1381-6

AUTHOR(S): Grines CL; Schreiber TL; Savas V; Jones DE; Zidar FJ; Gangadharan V; Brodsky M; Levin R; Safian R; Puchrowicz-Ochocki S; Castellani MD; O'Neill WW

ABSTRACT: OBJECTIVES: The purpose of this study was to determine prospectively whether the differences in anticoagulant and antiplatelet effects of ionic and nonionic contrast media after angiographic or clinical outcomes in patients with unstable ischemic syndromes undergoing percutaneous transluminal coronary angioplasty. BACKGROUND: The interaction of platelets and thrombin with the endothelium of injured vessels contributes to thrombosis and restenosis after coronary angioplasty. Case reports and retrospective observations have reported an increased risk of thrombosis with the use of nonionic contrast media. METHODS: A total of 211 patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty were randomized to receive nonionic or ionic low osmolar contrast media. Coronary angiograms were assessed by a technician blinded to the study contrast media, and clinical events were monitored by an independent nurse for 1 month. RESULTS: Patients receiving the ionic media were significantly less likely to experience decreased blood flow during the procedure (8.1% vs. 17.8%, p = 0.04). After the angioplasty, residual stenosis, vessel patency, the incidence of moderate to large thrombi and use of adjunctive thrombolytic therapy were similar between the two groups. However, patients receiving ionic media had fewer recurrent ischemic events requiring repeat catheterization (3.0% vs. 11.4%, p = 0.02) and repeat angioplasty during the initial hospital stay (1.0% vs. 5.8%, p = 0.06). One month after angioplasty, patients receiving ionic contrast media reported significantly fewer symptoms of any angina (8.5 vs. 20.0%, p = 0.04) or of angina at rest (1.4% vs. 11.8%, p = 0.01) and a reduced need for subsequent bypass surgery (0% vs. 5.9%, p = 0.04), compared with patients receiving the nonionic media. CONCLUSIONS: These findings demonstrate that in patients with unstable ischemic syndromes undergoing coronary angioplasty, the use of ionic low osmolar contrast media reduces the risk of ischemic complications acutely and at 1 month after the procedure. Therefore, low osmolar ionic contrast media should be strongly considered when performing interventions in patients with unstable angina or myocardial infarction.

ARTICLE TITLE: Management of unstable angina: the role of noninvasive risk stratification.

ARTICLE SOURCE: J Nucl Cardiol (United States), Mar-Apr 1997, 4(2 Pt 2) pS164-8


ABSTRACT: Many cardiologists rely primarily on catheterization to evaluate, and revascularization to treat, patients with unstable angina. In this era of managed care and cost containment, it is useful to determine whether some patients with unstable angina might benefit sufficiently from noninvasive testing and medical therapies. Several studies provide evidence that myocardial perfusion imaging is valuable for evaluating cardiac risk and thus determining the best candidates for medical treatment. Comparative studies indicate that myocardial perfusion imaging is superior to stress electrocardiography for assessing risk in patients with unstable angina.

ARTICLE TITLE: Prognostic value of predischarge dipyridamole technetium 99m sestamibi myocardial tomography in medically treated patients with unstable angina.

ARTICLE SOURCE: Am Heart J (United States), Oct 1995, 130(4) p734-40

AUTHOR(S): Stratmann HG; Tamesis BR; Younis LT; Wittry MD; Amato M; Miller DD

ABSTRACT: Recently developed unstable angina clinical practice guidelines have recommended risk stratification with dipyridamole thallium-201 myocardial imaging in patients at "intermediate" pretest clinical risk who cannot exercise maximally. The prognostic value of predischarge dipyridamole technetium 99m sestamibi (MIBI) tomography has not been assessed in this clinical setting. To this end, 128 medically treated patients with unstable angina at intermediate pretest clinical risk underwent follow-up for 16 +/- 11 (mean +/- SD) months after predischarge intravenous dipyridamole MIBI tomography. An abnormal MIBI scan result was present in 99 patients (77%), of whom 47 had one or more reversible and 76 had one or more fixed perfusion defects. Cardiac events occurred in 68 (53%) patients after dipyridamole testing: recurrent unstable angina (n = 36), nonfatal acute myocardial infarction (n = 6), or death (n = 26). A cardiac event occurred in 10% of patients with normal MIBI tomography results compared with 69% of those with abnormal results (p 0.01). Event rates associated with specific perfusion defects were similar (reversible = 68%; fixed = 71%) and were greater than rates in patients without defects (both p 0.05). Clinical variables associated with increased risk of cardiac events by univariate analysis included a history of congestive heart failure, prior myocardial infarction, and diabetes mellitus (all p 0.05). Independent multivariable predictors (Cox proportional hazards model) of any cardiac event were an abnormal result of MIBI scan (relative risk [RR] = 4.3, 95% confidence interval [CI] 1.5 to 12.0) and a reversible (RR = 1.8, 95% CI 1.1 to 2.9) or a fixed perfusion defect (RR = 2.9, 95% CI 1.6 to 5.4).(ABSTRACT TRUNCATED AT 250 WORDS).

ARTICLE TITLE: Rapid angiographic progression of coronary artery disease in patients with angina pectoris. The role of complex stenosis morphology.

ARTICLE SOURCE: Circulation (United States), Oct 15 1995, 92(8) p2058-65

AUTHOR(S): Kaski JC; Chester MR; Chen L; Katritsis D

ABSTRACT: BACKGROUND: Rapid disease progression commonly underlies acute coronary events, and "complex" stenosis morphology may play a role in this phenomenon. METHODS AND RESULTS: We studied the role of complex stenosis morphology in rapid disease progression in 94 consecutive patients awaiting routine coronary angioplasty. Coronary arteriography was repeated at 8 +/- 3 months' follow-up, immediately preceding angioplasty (68 patients) or after an acute coronary event (26 patients). Disease progression of 217 stenoses, of which 79 (36%) were "complex" and 138 (64%) were "smooth," was assessed by computerized angiography. At presentation, 63 patients had stable angina pectoris and 31 had unstable angina that settled rapidly with medical therapy. At follow-up, 23 patients (24%) had progression of preexisting stenoses and 71 (76%) had no progression. Patients with progression were younger (55 +/- 12 years) than those without (58 +/- 9 years) but did not differ with regard to risk factors, previous myocardial infarction, or severity and extent of coronary disease. Twenty-three lesions (11%) progressed, 15 to total occlusion (11 complex and 4 smooth; 65%). Progression occurred in 17 of the 79 complex stenoses (22%) and in 6 of the 138 smooth lesions (4%) (P = .002). Mean stenosis diameter reduction was also significantly greater in complex than in smooth lesions (11.6% versus 3.9% change; P .001). Acute coronary events occurred in 57% of patients with progression compared with 18% of those without progression (P .001) and were more frequent in patients who presented with unstable angina (P = .002). CONCLUSIONS: Rapid stenosis progression is not uncommon, and complex stenoses are at risk more than smooth lesions.

ARTICLE TITLE: Prognostic evaluation of patients after myocardial infarction: incremental value of sestamibi single-photon emission computed tomography and echocardiography.

ARTICLE SOURCE: J Nucl Cardiol (United States), Mar-Apr 1997, 4(2 Pt 1) p117-24

AUTHOR(S): Zanco P; Zampiero A; Favero A; Borsato N; Chierichetti F; Rubello D; Ferlin G

ABSTRACT: BACKGROUND: This study compares the prognostic value of 99mTc-labeled methoxyisobutyl isonitrile (MIBI) single-photon emission computed tomographic (SPECT) imaging, echocardiography, and other clinical and laboratory prognostic factors in the long-term risk stratification of patients with stable uncomplicated infarcts. METHODS AND RESULTS: Ninety-one consecutive patients affected by a first myocardial infarction without serious complications were enrolled. After at least 3 months from the infarction, they were submitted to stress-rest MIBI SPECT and rest echocardiography. Eighty-six patients completed a follow-up of at least 4 years (range 48 to 72 months; mean 55 months). By univariate (log-rank test) and multivariate analysis (Cox proportional hazards model), the main clinical, electrocardiographic, scintigraphic, and echocardiographic findings were evaluated and correlated statistically with the incidence of ensuing cardiac events. Twenty-five patients had cardiac events during the follow-up (four cardiac deaths, four myocardial infarctions, and 17 cases of unstable angina). At the multivariate analysis, the presence of reversible defects on MIBI SPECT (p = 0.008 and relative risk [RR] = 7.09), the wall motion score index, and the ejection fraction at echocardiography (respectively, p = 0.010, RR = 3.67, p = 0.036, and RR = 3.12), and stress angina (p = 0.007 and RR = 3.40) were significant and independent prognostic factors. CONCLUSIONS: In our long-term follow-up, MIBI SPECT and echocardiography appeared to be significant and independent prognostic tools in the risk stratification of patients with stable, uncomplicated infarcts, furnishing complementary information. The reversibility of MIBI defects appeared the best indicator for a bad prognosis.

ARTICLE TITLE: Prognostic value of exercise 201Tl tomography in patients treated with thrombolytic therapy during acute myocardial infarction.

ARTICLE SOURCE: Circulation (United States), Dec 1 1996, 94(11) p2735-42

AUTHOR(S): Dakik HA; Mahmarian JJ; Kimball KT; Koutelou MG; Medrano R; Verani MS

ABSTRACT: BACKGROUND: Although myocardial perfusion scintigraphy is of proven value in the risk stratification of patients with a recent myocardial infarction who receive conventional therapy, its value in patients undergoing thrombolytic therapy remains controversial. METHODS AND RESULTS: Seventy-one patients who received thrombolytic therapy for acute myocardial infarction had exercise 201Tl tomography and coronary angiography before hospital discharge. Eleven (15%) of 71 patients had ischemic ST-segment depression during exercise, whereas 27 patients (38%) had scintigraphic ischemia. Twenty-five (37%) of 68 patients had a cardiac event consisting of either death (n = 2), recurrent myocardial infarction (n = 5), congestive heart failure (n = 7), or unstable angina (n = 11) during a follow-up of 26 +/- 18 months. Univariate predictors of cardiac events were as follows: Killip class (P = .04); left ventricular ejection fraction (P .0005); total (P = .002) and ischemic (P .0005) perfusion defect size; percent thallium lung uptake (P = .001); presence of infarct-zone redistribution (P = .02); and multivessel coronary artery disease (P = .01). By multivariate analysis, the significant joint predictors of risk were ejection fraction (P .0005) and ischemic perfusion defect size (P = .005). The combination of ejection fraction and thallium tomography added significant incremental prognostic information to the clinical data, whereas angiography did not further improve a model that included clinical, ejection fraction, and tomographic variables. CONCLUSIONS: Quantitative exercise 201Tl tomography provides important incremental, long-term prognostic information in patients receiving thrombolytic therapy for acute myocardial infarction.

VANQWISH TRIAL: results are supported by many other studies

Use and Overuse of Angiography and Revascularization for Acute Coronary Syndromes (with references at the end)


The New England Journal of Medicine -- June 18, 1998 -- Volume 338, Number 25

Over the past two decades, clinical and pathological studies have examined the pathophysiology of the acute coronary syndromes, unstable angina, and non-Q-wave and Q-wave myocardial infarction. In these conditions, rupture of atherosclerotic plaques leads to varying amounts of platelet adhesion and aggregation, vasoconstriction, and the formation of partially or totally occlusive thrombus. Although the inhibition of platelet aggregation and thrombus formation and the restoration of antegrade flow in occluded coronary arteries improve survival and reduce the incidence of recurrent ischemia and infarction, residual coronary-artery stenosis may cause ischemia, infarction, or even death. As a result, there has been considerable interest in the routine use of coronary angiography and percutaneous revascularization in patients with these syndromes, in the hope of reducing the risk of adverse events.

The publication of the results of the Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial in this issue of the Journal (1) brings to four the number of large prospective, randomized studies comparing "aggressive" and "conservative" management of acute coronary syndromes. Together, these trials have studied more than 6400 patients with unstable angina, (2,3) non-Q-wave infarction, (1,2,3) or Q-wave infarction treated with thrombolytic therapy (4,5,6) who have been assigned to routine aggressive management or to a more conservative strategy, in which angiography and revascularization are performed only in patients with spontaneous or provokable myocardial ischemia (i.e., ischemia-guided therapy). With remarkable clarity and consistency, all four studies show that routine angiography and revascularization do not reduce the incidence of nonfatal reinfarction or death as compared with the more conservative, ischemia-guided approach. In fact, in the VANQWISH study of patients with non-Q-wave infarction, (1) the aggressive strategy (which these investigators call "invasive") was associated with increased mortality during hospitalization, at one month, and at one year.

Although all four trials (1,2,3,4,5,6) found that the incidence of adverse events was similar (or greater) in patients whose acute coronary syndromes were managed aggressively than in those assigned to conservative management, an aggressive approach continues to be chosen by most physicians in the United States, whereas a conservative strategy is more likely to be followed in Canada and Europe. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, (7) which was performed in the United States and abroad, four thrombolytic regimens were compared in patients with Q-wave infarction. After each patient had received one of the four thrombolytic regimens, treatment was determined by his or her own physician.

Although the patients enrolled in the United States were more likely than their Canadian counterparts to undergo coronary angiography (68 percent vs. 35 percent, respectively) and subsequent revascularization (31 percent vs. 12 percent), the incidence of reinfarction and death during more than three years of follow-up was similar. (8) The chief predictors of the decision by U.S. physicians to use coronary angiography were a relatively young age of the patient and the availability of a catheterization facility. Furthermore, there was marked regional variation within the United States in the rates of use of angiography and revascularization, (9) which was not explained by differences in the characteristics of the patients or the incidence of complications of myocardial infarction. A strong relation was noted between the availability of angiography in a geographic area and the likelihood that aggressive management would be chosen. However, the increased use of invasive procedures did not reduce the incidence of recurrent infarction or death.

Why are coronary angiography and revascularization often performed in patients with acute coronary syndromes in the United States, even without an obvious indication? Several factors may be responsible. First, in an era in which invasive cardiac procedures are manifestations of high-technology, resource-intensive medical care, many patients and their family members expect and insist on aggressive management. The term "conservative management" may project the impression (to physicians and patients alike) of obsolescence, inadequacy, and inferiority rather than of thoughtful reflection and the application of scientifically based, ischemia-guided therapy. In the event of an adverse outcome, the patient and his or her family may be more understanding and forgiving if an aggressive approach was pursued (i.e., if "everything possible was done"), even if such an approach contributes, directly or indirectly, to the adverse outcome. In the GUSTO trial, (7) physicians in the United States more often reported that requests by the patient or family members as well as concern about liability influenced them to pursue aggressive management than did their Canadian counterparts. (8)

Second, some physicians in the United States express skepticism about the applicability of the results of the aforementioned trials to their patients. In the three randomized comparisons of aggressive and conservative management strategies conducted in the United States, (1,2,4) 70 to 80 percent of the patients initially assigned to conservative management nonetheless underwent coronary angiography during or shortly after their index hospitalization (9,10); in many cases, angiography was recommended without a clear indication. Of the physicians in the United States who participated in the GUSTO trial who were surveyed, (8) 54 percent said they routinely recommended coronary angiography for survivors of uncomplicated myocardial infarction, 71 percent did so for those receiving thrombolytic therapy, and 93 percent did so for survivors of infarction who were less than 45 years old, even though these groups of patients are at low risk for subsequent complications regardless of the manner in which they are treated. In Europe and Canada, (8,11) in contrast, patients who received thrombolytic therapy and were assigned to conservative management underwent angiography and revascularization one third to one half as often as their U.S. counterparts, yet their outcome was similar, and routine aggressive management offered no substantial benefit.

Third, studies that substantiate preconceived notions are likely to be embraced and their recommendations followed, whereas those that do not are often ignored. For example, primary angioplasty for acute myocardial infarction is widely used and enthusiastically advocated, yet direct comparisons with thrombolytic therapy in relatively small numbers of patients showed, at best, only a small benefit of angioplasty, and larger studies showed none. (12) Many physicians in the United States, even today, continue to believe that all patients with acute coronary syndromes are best treated with prompt coronary angiography and revascularization, despite the absence of scientific support for such an approach.

Fourth, as compared with Canada and Europe, the United States has an abundance of facilities for prompt angiography and revascularization, physicians trained to perform these procedures, and monetary remuneration to the facilities and physicians. The combination of these factors encourages the use of angiography and revascularization without a clear indication. Physicians who work in hospitals with catheterization facilities are more likely to recommend coronary angiography than those without easy access to such a facility. (9,10,11) Cardiologists are more likely to recommend angiography than internists, and cardiologists who perform angiography are even more likely than their colleagues who do not perform the procedure to recommend it. (8,10,13)

At present, particularly in the United States, a substantial number of patients with acute coronary syndromes undergo coronary angiography and revascularization without a clear indication. Which patients with unstable angina or myocardial infarction should undergo angiography? First, those who have spontaneous or provokable ischemia despite reasonable medical therapy should undergo invasive evaluation and revascularization. For these patients, angiography and revascularization are clearly indicated and beneficial. Second, symptomatic patients or those with evidence from noninvasive tests of left ventricular systolic dysfunction should undergo angiography, with the goal of identifying those who would be expected to benefit from subsequent surgical revascularization. (14) The treatment of patients whose course is uncomplicated should be guided by the results of the relevant trials, (1,2,3,4,5,6) such as VANQWISH, (1) rather than physicians' preference or other, nonmedical incentives.

Richard A. Lange, M.D. L. David Hillis, M.D. University of Texas Southwestern Medical Center

Dallas, TX 75235-9047

References to the article of Dr. Lange

1. Boden WE, O'Rourke RA, Crawford MH, et al. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. N Engl J Med 1998;338:1785-92.

2. Williams DO, Braunwald E, Thompson B, Sharaf BL, Buller CE, Knatterud GL. Results of percutaneous transluminal coronary angioplasty in unstable angina and non-Q-wave myocardial infarction: observations from the TIMI IIIB Trial. Circulation 1996;94:2749-55.

3. Anderson HV, Cannon CP, Stone PH, et al. One-year results of the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial: a randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q wave myocardial infarction. J Am Coll Cardiol 1995;26:1643-50.

4. The TIMI Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) phase II trial. N Engl J Med 1989;320:618-27.

5. Terrin ML, Williams DO, Kleiman NS, et al. Two-and three-year results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II clinical trial. J Am Coll Cardiol 1993;22:1763-72.

6. SWIFT (Should We Intervene Following Thrombolysis?) Trial Study Group. SWIFT trial of delayed elective intervention v conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. BMJ 1991;302:555-60.

7. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-82.

8. Pilote L, Granger C, Armstrong PW, Mark DB, Hlatky MA. Differences in the treatment of myocardial infarction between the United States and Canada: a survey of physicians in the GUSTO trial. Med Care 1995;33:598-610.

9. Pilote L, Califf RM, Sapp S, et al. Regional variation across the United States in the management of acute myocardial infarction. N Engl J Med 1995;333:565-72.

10. Pilote L, Miller DP, Califf RM, Rao JS, Weaver WD, Topol EJ. Determinants of the use of coronary angiography and revascularization after thrombolysis for acute myocardial infarction. N Engl J Med 1996;335:1198-205.

11. Van de Werf F, Topol EJ, Lee KL, et al. Variations in patient management and outcomes for acute myocardial infarction in the United States and other countries: results from the GUSTO trial. JAMA 1995;273:1586-91.

12. Lange RA, Hillis LD. Should thrombolysis or primary angioplasty be the treatment of choice for acute myocardial infarction? Thrombolysis -- the preferred treatment. N Engl J Med 1996;335:1311-2.

13. Every NR, Larson EB, Litwin PE, et al. The association between on-site cardiac catheterization facilities and the use of coronary angiography after acute myocardial infarction. N Engl J Med 1993;329:546-51.

14. Alderman EL, Bourassa MG, Cohen LS, et al. Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation 1990;82:1629-46.

Results of percutaneous transluminal coronary angioplasty in unstable angina and non-Q-wave myocardial infarction. Observations from the TIMI IIIB Trial.

Circulation 1996 Dec 1;94(11):2749-2755

Williams DO, Braunwald E, Thompson B, Sharaf BL, Buller CE, Knatterud GL

Department of Medicine, Rhode Island Hospital, School of Medicine, Brown University, Providence 02903, USA.

BACKGROUND: This report describes the results of percutaneous transluminal coronary angioplasty (PTCA) in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB Investigation. METHODS AND RESULTS: PTCA was performed before hospital discharge in 444 of 1473 patients with either unstable angina pectoris or non-Q-wave myocardial infarction (NQWMI) enrolled in TIMI IIIB. Angiographic success was observed in 96.1% of patients. For the entire cohort, the cumulative incidences of death and infarction at 1 year were 2.0% and 8.2%, respectively. The periprocedural incidence of myocardial infarction was 2.7%; emergency coronary bypass surgery, 1.4%; and death, 0.5%. By 1 year of follow-up, 122 patients (28.0%, Kaplan-Meier) had an additional revascularization procedure, 75 (61.5%) had PTCA only, 30 (24.6%) had coronary bypass surgery only, and 17 (13.9%) had both procedures. The results of PTCA were not improved by routine pretreatment with intravenous tissue plasminogen activator (TPA). Periprocedural myocardial infarction was more common among patients receiving TPA than placebo (odds ratio [OR], 2.19; P = .03) and among those with unstable angina than those with NQWMI (OR, 15.5; P = .007). No difference in outcome was observed when patients were analyzed according to age (OR, 1.06; P = .092) or sex (OR, 1.54; P = .51). Variables predictive of poor outcome were PTCA within the first 24 hours of enrollment, PTCA site being the left anterior descending coronary artery, and unsuccessful angiography. CONCLUSIONS: In TIMI IIIB, PTCA was performed for patients with unstable angina and NQWMI with a very high rate of angiographic success and a low incidence of complications. By 1 year, repeat revascularization was performed in 28.0% of patients. Routine pretreatment with thrombolysis did not enhance outcome.

One-year results of the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial. A randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q wave myocardial infarction.

J Am Coll Cardiol 1995 Dec;26(7):1643-1650

Anderson HV, Cannon CP, Stone PH, Williams DO, McCabe CH, Knatterud GL, Thompson B, Willerson JT, Braunwald E

University of Texas Health Science Center, Houston 77225, USA.

OBJECTIVES. We report mortality, infarction, revascularization and repeat hospital admission events for 1 year after enrollment and randomization in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB clinical trial. BACKGROUND. The purpose of this trial was to investigate the role of a thrombolytic agent added to conventional medical therapies and to compare an early invasive management strategy to a more conservative early strategy in patients with unstable angina and non-Q wave myocardial infarction. METHODS. There were 1,473 patients enrolled, and they received conventional anti-ischemic medical therapies. They were randomized to therapy with either tissue-type plasminogen activator (t-PA) or placebo and also to an early invasive management strategy with coronary arteriography at 18 to 48 h, followed by revascularization as soon as possible if appropriate, or, alternatively, to an early conservative strategy with arteriography and revascularization reserved for failure of initial therapy to prevent recurrent ischemia. The primary end point was a composite outcome variable and was assessed at 42 days. Patients were then managed entirely at the discretion of their treating physician. Follow-up contacts were made at 1 year. RESULTS. The incidence of death or nonfatal infarction for the t-PA- and placebo-treated groups was similar after 1 year (12.4% vs. 10.6%, p = 0.24). The incidence of death or nonfatal infarction was also similar after 1 year for the early invasive and early conservative strategies (10.8% vs. 12.2%, p = 0.42). A trial of this size should be able to detect differences in relative risk for death or infarction > or = 1.81 with a power of 80% at a significance level (alpha) of 0.01. Revascularization by 1 year was common, but was slightly more common with the early invasive than the early conservative strategy (64% vs. 58%, p < 0.001). This result was related entirely to a small difference in angioplasty rates (39% vs. 32%, p < 0.001) inasmuch as rates of bypass grafting by 1 year were equivalent (30% in each group, p = 0.50). The high rate of revascularization in both strategies was accompanied by comparable clinical status at the 1-year follow-up contact. CONCLUSIONS. In this large study of unstable angina and non-Q wave myocardial infarction, the incidence of death and nonfatal infarction or reinfarction was low but not trivial after 1 year (4.3% mortality, 8.8% nonfatal infarction). An early invasive management strategy was associated with slightly more coronary angioplasty procedures but equivalent numbers of bypass surgery procedures than a more conservative early strategy of catheterization and revascularization only for signs of recurrent ischemia. The incidence of death or nonfatal infarction, or both, did not differ after 1 year by strategy assignment, but fewer patients in the early invasive strategy group underwent later repeat hospital admission (26% vs. 33%, p < 0.001). Either strategy is appropriate for patient management; differences in hospital admissions and revascularization procedures, with their attendant costs, are likely to be minimal.

Two- and three-year results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II clinical trial.

J Am Coll Cardiol 1993 Dec;22(7):1763-1772

Terrin ML, Williams DO, Kleiman NS, Willerson J, Mueller HS, Desvigne-Nickens P, Forman SA, Knatterud GL, Braunwald E

Maryland Medical Research Institute, Baltimore 21210.

OBJECTIVES. This report describes the survival and reinfarction rates for 2- and 3-year follow-up in the Thrombolysis in Myocardial Infarction (TIMI) Phase II clinical trial. BACKGROUND. Patients enrolled in TIMI II were randomly assigned to an invasive (1,681 patients) or a conservative (1,658 patients) management strategy to follow receipt of intravenous recombinant tissue-type plasminogen activator for acute myocardial infarction. METHODS. Eligibility required presentation within 4h of onset of symptoms and at least 1-mV ST segment elevation in two contiguous electrocardiographic leads. The invasive strategy group underwent cardiac catheterization 18 to 48 h after study entry and, when appropriate, percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. In the conservative strategy group these diagnostic and revascularization procedures were reserved for recurrent spontaneous ischemia or ischemia on low level exercise at the time of hospital discharge. RESULTS. Complete 2-year follow-up data are available for 3,187 patients (95.4%). Cumulative life-table rates of death or reinfarction were 17.6% for the invasive strategy group and 17.9% for the conservative strategy group (p = NS) and mortality was 8.9% and 8.7% (p = NS), respectively. Complete data are available for 1,959 (90.1%) of the 2,174 patients enrolled for 3 years. Rates of death or reinfarction were 21.0% for the invasive strategy group with 20.0% for the conservative strategy group (p = NS), with mortality of 11.5% and 11.0% (p = NS), respectively. In this cohort, the mortality was 1.3% in the 2nd year and 1.7% in the 3rd year from study entry. CONCLUSIONS. TIMI II invasive and conservative strategies resulted in similar favorable outcomes after 2 and 3 years. Mortality and reinfarction rates in the two strategies were comparable. Deaths were infrequent in the 2nd and 3rd years from study entry.

SWIFT trial of delayed elective intervention v conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. SWIFT (Should We Intervene Following Thrombolysis?) Trial Study Group.

BMJ 1991 Mar 9;302(6776):555-560

OBJECTIVE--To see whether early elective angiography with a view to coronary angioplasty or bypass grafting of a stenosed infarct related vessel would improve outcome in acute myocardial infarction treated by thrombolysis with anistreplase. DESIGN--Randomised study of two treatment strategies with analysis of results over 12 months. SETTING--21 district hospitals and regional cardiac centres in Britain and Ireland. SUBJECTS--800 of 993 patients presenting with clinical and electrocardiographic features of acute myocardial infarction up to three hours after the onset of major symptoms. TREATMENT STRATEGIES--Intravenous anistreplase 30 units followed by a standard regimen of heparin, warfarin, and timolol and (in patients so randomised) early angiography plus appropriate intervention. MAIN OUTCOME MEASURE--Death or reinfarction within 12 months. RESULTS--397 patients were randomised to receive early angiography plus appropriate intervention (coronary angioplasty in 169 cases, coronary grafting in 59) and 403 patients to receive conservative care (of these, 12 had angioplasty and seven bypass grafting during the initial admission). By 12 months mortality (5.8% (23 patients) in the intervention group v 5.0% (20) in the conservative care group; p = 0.6) and rates of reinfarction (15.1% (60 patients) v 12.9% (52); p = 0.4) were similar in the two groups. No significant differences in rates of angina or rest pain were found at 12 months. Left ventricular ejection fraction at three and 12 months was the same in both groups. Median hospital stay was longer in the intervention group (11 days v 10 days; p less than 0.0001). CONCLUSION--For most patients given thrombolytic treatment for acute myocardial infarction a strategy of angiography and intervention is appropriate only when required for clinical indications.

Regional Variation across the United States in the Management of Acute Myocardial Infarction

The New England Journal of Medicine -- August 31, 1995 -- Volume 333, Number 9

Louise Pilote, Robert M. Califf, Shelly Sapp, Dave P. Miller, Daniel B. Mark, W. Douglas Weaver, Joel M. Gore, Paul W. Armstrong, E. Magnus Ohman, Eric J. Topol, for the GUSTO-1 Investigators

ABSTRACT: BACKGROUND: Differences in the management of acute myocardial infarction have been reported among countries, but few studies have investigated this issue in regions of the United States. METHODS: We compared the management of acute myocardial infarction among census regions across the United States, using data from the first Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial (GUSTO-1) comprising 21,772 patients, and from the American Hospital Association. RESULTS: We found substantial regional variation in the management of acute myocardial infarction in the United States. Beta-blockers (prescribed for a range of 55 to 81 percent of patients in the various regions), nitrates (prescribed for 61 to 77 percent), and angiotensin-converting-enzyme inhibitors (prescribed for 18 to 23 percent) were used most often in New England, whereas calcium-channel blockers (31 to 42 percent) and lidocaine (14 to 43 percent) were used least often there. Similarly, the proportion of patients undergoing various cardiac procedures differed among regions (range for angiography, 52 to 81 percent of patients; angioplasty, 22 to 35 percent; and coronary-artery bypass surgery, 9 to 17 percent) and was lowest in New England. The regional use of cardiac procedures was closely related to their availability, except in New England. After the analysis was adjusted for clinical and hospital variables, patients in New England were found to be less likely to undergo angiography than patients in the other regions (odds ratio, 0.37; 95 percent confidence interval, 0.32 to 0.42). There was no apparent relation between the use of cardiac procedures and rates of recurrent infarction or death at 30 days or 1 year. CONCLUSIONS: There is substantial regional variation in the use of cardiac medications and procedures to manage acute myocardial infarction in the United States. The use and availability of cardiac procedures are closely related. The management of acute myocardial infarction in New England is atypical in that the relatively limited availability of cardiac procedures does not account for their relatively low use in that region.

Variations in the utilization of coronary angiography for elderly patients with an acute myocardial infarction. An analysis using hierarchical logistic regression.

Med Care (United States), Jun 1995, 33(6) p625-42

AUTHOR(S): Gatsonis CA; Epstein AM; Newhouse JP; Normand SL; McNeil BJ

ABSTRACT: This article reports a study of variations in the utilization of angiography for Medicare recipients who had an acute myocardial infarction. The study cohort consisted of 1987 Medicare beneficiaries who had a recent acute myocardial infarction. Variations were examined from three perspectives: patient characteristics, regional practice patterns, and on-site availability of the procedure. Factors associated with variation within and among states were incorporated into the analysis using hierarchical logistic regression models. The probability of angiography during the first 90 days after an acute myocardial infarction was estimated as a function of patient age, gender, race, and comorbidity for patients in 51 states (including the District of Columbia). Interstate differences were examined in relation to geographic region and on-site availability of angiography. Observed rates of angiography ranged between 13.8% and 38.3% (median, 24.7%). Variation was nearly threefold based on estimated state probabilities of angiography for a patient with characteristics set at the national average. Observed and estimated rates were lower in northeastern states than in other parts of the United States. States with more extensive onsite availability of angiography tended to have higher angiography rates after adjusting for patient characteristics and geographic region. Adjusted angiography rates were on average higher for younger patients, males, and nonblacks. There was substantial interstate variation in race differences, with states in the Southeast generally having the largest differences. The adjusted black-to-nonblack odds ratio ranged from a low of 0.41 to a high of 0.94. Interstate variation in age and gender differences was moderate. The work reported in this article illustrates the potential of hierarchical regression modeling as a framework for the analysis of variations and some methodologic issues connected with its implementation. Our results show that large variations in the utilization of procedures can exist, despite uniform insurance coverage and a relatively homogeneous patient cohort. Aggressive use of angiography was highly variable across states as was the degree of access to the procedure for blacks and nonblacks. The state rate of on-site availability of angiography facilities was an important predictor of utilization. Increased on-site availability of angiography, however, was not associated with a reduction of differences in access to the procedure.

Variations in patient management and outcomes for acute myocardial infarction in the United States and other countries. Results from the GUSTO trial. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.

JAMA 1995 May 24;273(20):1586-1591

Van de Werf F, Topol EJ, Lee KL, Woodlief LH, Granger CB, Armstrong PW, Barbash GI, Hampton JR, Guerci A, Simes RJ, et al

Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium.

OBJECTIVE--To examine differences in outcomes and patient management between patients in the United States and outside the United States undergoing thrombolysis for acute myocardial infarction. DESIGN, SETTING, AND PATIENTS--Patients in the United States (n = 23,105) and 14 other countries (n = 17,916) were randomized to receive streptokinase plus either subcutaneous or intravenous (IV) heparin, accelerated recombinant tissue-type plasminogen activator (rt-PA) plus IV heparin, or combined streptokinase and rt-PA plus IV heparin. OUTCOME MEASURES--Differences in 30-day mortality and patient management were compared among treatments and between US and non-US patients. Treatment-by-country interactions were assessed by logistic regression analyses. Expected mortality of US and non-US patients was estimated using a predictive model and was compared with observed mortality. RESULTS--Mortality reduction with accelerated rt-PA vs streptokinase was greater in the United States (1.2% absolute decrease vs 0.7% elsewhere), but the test for treatment-by-country interaction against streptokinase was not significant (P = .30). Benefits of accelerated rt-PA over combination therapy were observed in the United States, but not in other countries (P = .02). Despite differences in base-line characteristics and patient management, 30-day mortality was not significantly different: 6.8% in the United States vs 7.2% elsewhere (P = .09). After adjustment for baseline differences, observed vs predicted outcomes were slightly better in the United States (6.8% vs 7.0%) than elsewhere (7.2% vs 7.0%), indicating that enrollment in the United States was a marginally significant predictor of better survival (P = .047). CONCLUSIONS--No significant evidence for a differentially greater benefit of accelerated rt-PA over streptokinase was found in US vs non-US patients. However, increased procedure and treatment use in the United States was associated with only a small decrease in short-term mortality. Long-term follow-up is required to clarify the relationship between survival and the more intensive US management approach.

Should Thrombolysis or Primary Angioplasty Be the Treatment of Choice for Acute Myocardial Infarction?

The New England Journal of Medicine -- October 24, 1996 -- Volume 335, Number 17

In a community-based study reported in this issue of the Journal, Every et al. compared the benefits of thrombolytic therapy with those of primary coronary angioplasty for acute myocardial infarction. Although earlier trials had suggested that primary angioplasty may be superior, Every et al. found the two approaches essentially equivalent. How should physicians choose between them?

We solicited two opposing opinions, along with rebuttals, which we present in the first of a new series of occasional pieces called "Clinical Debate." Lange and Hillis argue that thrombolytic therapy should be the initial therapy, whereas Grines favors coronary angioplasty. Is there a single, right answer? Readers will have to judge for themselves.


The published guidelines of the European Society of Cardiology for the management of Angina Pectoris and Acute Myocardial Infarction:

go to: http://www.escardio.org