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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

80th Scientific Sessions of the American Heart Association

Orlando, Florida / November 4-7, 2007

Reported by: Robert C. Welsh, MD, FRCPC

Interventional Cardiologist

Director, Cardiology Residency Training Program

Co-director, Chest Pain Program

University of Alberta Edmonton, Alberta

Two broad therapeutic options exist for patients with ST-segment elevation myocardial infarction (STEMI): percutaneous coronary intervention (PCI) and lytic therapy. Dr. Tim Henry, Minneapolis Heart Institute Foundation, Minnesota, made a case for PCI as the better approach. In support of his argument, Dr. Henry cited a meta-analysis of 23 clinical trials wherein the two treatment strategies were compared (Keeley et al. Lancet 2003;361(9351):13-20). For the composite end point of death, reinfarction and stroke, PCI had an overall event rate of 8% compared with 14% for thrombolytic therapy (P<0.0001). Moreover, PCI held a significant advantage over lytic therapy for each of the individual components of the composite end point (P=0.0004 to P<0.0001).

Registry and clinical trial data have demonstrated the advantages of prehospital administration compared to in-hospital administration of lysis. This has been confirmed within a large registry showing improved outcomes in those patients receiving prehospital vs. in-hospital fibrinolysis with primary PCI appearing as an attractive alternative to both lysis strategies (Stenestrand et al. JAMA 2006; 296(14):1749-56). Following fibrinolysis, studies have shown the advantage of dedicated rescue PCI after failed pharmacological reperfusion therapy compared to a conservative approach (REACT Trial). Although small randomized trials have suggested that lysis-facilitated PCI is an attractive strategy, the largest trials to date have not demonstrated a consistent advantage of lysis-facilitated PCI compared to primary PCI alone (FINESSE and ASSENT IV PCI).

Improving MI Outcomes: Role of Adjunctive Therapy

Regardless of whether STEMI is treated with thrombolysis or PCI, adjunctive therapies have a major role in promoting favourable outcomes. In a review of pharmacologic and adjunctive therapies for STEMI, Dr. Christopher Granger, Duke University Medical Center, Durham, North Carolina, presented data showing that adjunctive therapies administered in conjunction with fibrinolysis enhance sustained coronary artery patency. The combination of ASA, clopidogrel and enoxaparin in conjunction with fibrinolysis achieves sustained patency rates similar to those quoted in primary PCI research (CLARITY trial).

Dr. Granger also reviewed data that illustrated the potential role of fondaparinux compared to unfractionated heparin (UFH) or placebo as part of a clinical management for STEMI. In the OASIS-VI clinical trial, for example, early treatment with factor Xa inhibitors significantly reduced the 30-day risk of death or MI compared with usual care (Yusuf et al. JAMA 2006; 295(13):1519-30).

At the 2007 Transcatheter Cardiovascular Therapeutics meeting in October, results of the HORIZONS-AMI trial also demonstrated mixed results with UFH. The trial involved 3600 STEMI patients who underwent revascularization and stenting. Patients were randomized to receive UFH plus a glycoprotein IIb/ IIIa inhibitor or monotherapy with the thrombin inhibitor bivalirudin. Patients in the UFH arm had a significantly higher incidence of clinical events and major bleeding (P<0.0001) and a significantly higher 30-day mortality (P=0.048).

Dynamic Updating of Patient Risk

The ability to hone risk estimates on a continual basis could give clinicians another useful tool to apply to the management of patients with STEMI and help improve the odds of favourable outcomes. Dr. Elliott Antman, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, presented an example of dynamic updating patient risk, using data from the ExTRACT TIMI 25 trial.

Briefly, ExTRACT TIMI 25 was a multicentre, randomized clinical trial that compared the low molecular-weight heparin (LMWH) enoxaparin with UFH as adjunctive treatment for STEMI patients undergoing PCI after initial treatment with fibrinolysis (Antman et al. N Engl J Med 2006;354(14):1477-88). The primary end point was the composite of mortality and nonfatal MI at 30 days.

Treatment with enoxaparin resulted in a statistically significant 23% reduction in the primary end point (P=0.001). The difference was driven primarily by a 28% reduction in nonfatal MI among patients treated with the LMWH (P<0.001). Its advantages over UFH emerged within five days and continued throughout the 30-day follow-up period. Rates of adverse events were similar in the two treatment groups, with the exception of stroke, which occurred significantly more often with the UFH (P=0.006).

Here at the AHA scientific sessions, Dr. Antman presented findings from an examination of the feasibility of incorporating in-hospital events to produce an update of the TIMI risk score, which captures baseline prognostic information about patients with STEMI. A score (1 to 5) was assigned to each in-hospital event on the basis of its severity. The in-hospital events evaluated (and assigned score) were reinfarction (1 point), major bleeding (1 point), cardiac arrhythmia (2 points), new heart failure or cardiogenic shock (4 points) and stroke (5 points). The sum of in-hospital events was compared with the baseline TIMI risk score with respect to accuracy for predicting one-year mortality (Figure 1).

Figure 1. Updated TIMI Risk Score

The results showed that the occurrence or absence of in-hospital events changed estimated mortality. For example, a patient who had a baseline TIMI risk score of 4 (patient A) had a projected one-year mortality of 7.1%. If the patient had no in-hospital events, the mortality risk estimate decreased to 5.5%.

Consistent with the baseline risk estimates, the mortality risk estimate at hospital discharge increased with the risk score. A patient with a baseline risk score of ³9 (patient B) had a one-year estimated mortality risk of 27.6%. Even with no further events, the same patient would have a mortality risk of 30.1% at discharge.

The findings suggest that dynamic updating of the TIMI risk score is feasible and offers the potential to refine estimates of one-year mortality, which might be helpful in targeting complex or costly therapeutic interventions to patients who are likely to benefit the most from the intervention.

Cost-Effectiveness of Anticoagulation Strategies

Another analysis of data from the ExTRACT TIMI 25 study examined an issue of ever-increasing prominence in the delivery of quality health care: the cost of products, services and resources. Dr. William Weintraub, Christiana Care Health System, Newark, Delaware, presented data from a comparison of costs associated with use of enoxaparin or UFH.

The cost-effectiveness analysis incorporated four aspects of care that have implications for cost:

• Costs of the index and subsequent hospitalization for patients in each treatment group. Costs were derived from the US Medicare program’s diagnosis-related groups and average Medicare reimbursement.

• Post-discharge outpatient procedures. Costs were estimated from Current Procedural Terminology (CPT) codes and assigned a cost on the basis of Medicare reimbursement.

• Survival beyond the clinical trial. Estimates were derived from Framingham Heart Study data.

• Incremental cost-effectiveness of enoxaparin vs. UFH. Cost-effectiveness was expressed in terms of cost per life-year and quality-adjusted life year (QALY).

The analysis revealed a net reduction in 30-day hospital costs of $98.50 for patients treated with the LMWH. Lost life years, based on Framingham estimates, were significantly reduced with enoxaparin by approximately 12%. When costs beyond the trial period were considered, lifetime costs were about $500 more with enoxaparin. The incremental cost-effectiveness ratio of enoxaparin compared with UFH was $4369 per life-year gained. Dr. Weintraub reported that 99.9% of estimated costs per life-year gained fell below the $50,000 threshold historically used for determining cost-effectiveness.

On the basis of the analysis, Dr. Weintraub concluded that enoxaparin reduces mortality and nonfatal MI compared with UFH and is highly cost-effective for treatment of STEMI patients (Table 1).

Table 1. ExTRACT TIMI 25: Cost-EffectivenessElderly STEMI P
Reperfusion Therapy

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Changing demographics in most Western countries has resulted in a growing population of older patients, who are disproportionately represented in clinical trials of MI. As a consequence, the benefits of reperfusion are less well-defined in older patients as compared to younger populations.

Investigators headed by Dr. Nicolas Boudou, Ranguell Hospital, Toulouse, France, examined six-month mortality in STEMI patients ³75 years of age in the FAST-MI Registry, a study of patients admitted to intensive care units for acute MI during a one-month period in 2005. Review of data revealed 520 STEMI patients ³75 years old were admitted to intensive care units within 48 hours of symptom onset. The patients’ average age was 82.3 years and women accounted for 52.5% of the patients.

About one-quarter of the older patients underwent primary PCI, 9% had prehospital thrombolysis and 5.8% had in-hospital thrombolysis. The six-month mortality was 17.9% after PCI, 5.2% after prehospital lysis, 5.2% for in-hospital lysis and 71.6% for patients who received no reperfusion therapy (P=0.037).

By multivariate analysis, significant predictors of six-month mortality were smoking history, primary angioplasty, heart failure, anterior MI and systolic hypertension at admission. The authors concluded that in the absence of specific guidelines for treatment of older patients with STEMI, reperfusion therapy is associated with significant improvement in six-month survival.

Mixed Results witH Antiplatelet Therapy

With the emergence of primary stenting as preferred treatment for acute MI, the short- and long-term benefits of antiplatelet therapy with abciximab have become less certain, as compared with the agent’s use in primary angioplasty. In an effort to clarify the issue, Dr. Sujethra Vasu, State University of New York Health Science Center, Stony Brook, and colleagues reported findings from a meta-analysis of randomized clinical trials of abciximab in patients undergoing primary stenting for acute MI.

A literature review identified four clinical trials involving a total of 2137 patients, 1074 randomized to abciximab and 1063 to placebo. The analysis showed that active treatment significantly reduced the need for target vessel revascularization at 30 days (P=0.003) and resulted in a trend toward a lower risk of reinfarction (P=0.06) but had no effect on 30-day mortality. During long-term follow-up, the target vessel revascularization benefit was reduced to a trend (P=0.06) and neither reinfarction nor mortality was reduced.

Dr. Vasu and colleagues concluded that adequately powered randomized clinical trials are needed to clarify the role of adjunctive antiplatelet therapy with abciximab during primary stenting.

Summary

On the basis of the preceding discussion, several observations can be made:

• Primary PCI may offer advantages over lytic therapy for treatment of STEMI, but reperfusion by any means remains the principal objective in urgent treatment of patients.

• Adjunctive therapy can substantially affect outcomes in acute MI, regardless of the primary treatment.

• A patient’s estimated mortality risk can be refined in hospital by use of several key, easily identified clinical variables. The refinement can result in more accurate risk assessment and aid clinical decision-making.

• When choosing an anticoagulant, the LMWH enoxaparin reduces the risk of mortality and reinfarction and is cost-effective in comparison to an UFH.

• Older patients with STEMI benefit from reperfusion therapy and should be considered candidates for therapy in the absence of clear contraindications.

• The benefits of antiplatelet therapy with abciximab in STEMI patients undergoing primary angioplasty might not be easily extrapolated to the more contemporary interventional approach of primary stenting.