Chapter (6)

clinical trials

Acute Coronary Syndromes

COMPARISON OF MEDICAL THERAPY VERSUS INTERVENTIONAL APPROACH (PCI)

THERAPEUTIC APPROACHES

The course in patients with unstable angina and NSTEMI is unpredictable, some patients are at increased risk of developing MI or sudden death, however, the majority have a more benign course.

• Predictors of increased risk of future major cardiovascular events include old age, resting recent and recurrent angina, persistent ST- segment depression, elevated serum troponin, presence of multiple risk factors, history of previous MI, PCI or CABG, angina refractory to antiischemic therapy and angina associated with hemodynamic deterioration.
• There are currently two available therapeutic strategies, early invasive strategy of coronary angiography followed by revascularization if appropriate and a conservative strategy including intensifying medical therapy of aspirin, statins in large dose, clopidogrel, intravenous heparin or LMWH, intravenous nitroglycerin and beta blockers. GP IIb/IIIa inhibitors may be added in high risk patients. Persistence of symptoms, symptom recurrence, or a high positive stress test leads to prompt coronary angiography.
• Results of clinical trials were not uniform. Some showed a better outcome with conservative approach (VANQWISH) while the majority showed the reverse or no difference (figure 6-1).
• The best therapeutic strategy is to individualize therapy. High risk patients should follow invasive approach while low risk patients are treated conservatively.
• Risk stratification of patients presenting with UA/NSTEMI should be part of management strategy. Based upon risk category, decision whether to treat conservatively or invasively is made.  

 

Figure (6-1): Trials of Intervention in Acute Coronary Syndromes

IMPORTANT CLINICAL TRIALS

• TIMI IIIB Trial (1994)
  • 1473 patients seen within 24 hours of an episode of rest angina and randomly assigned to tissue-type plasminogen activator (TPA) or placebo, and to conservative or early invasive approach.
  • There was no significant difference in the rates of death and non-fatal MI between invasive and conservative therapy at 6 weeks or one year.
  • There was a high cross over to invasive therapy in the conservative group.
• VANQWISH Trial (1998)
  • 920 patients with NSTEMI.
  • There was no additional benefit from the invasive approach.
  • At the time of hospital discharge and at one year, the primary end point of death or nonfatal MI occurred significantly more frequently in the invasive group.
  • At two years, there was no significant difference between the two groups.
  • Three groups did worse with early invasive therapy:
    1. Those who received thrombolysis.
    2. Those without ST segment depression.
    3. Those without a prior MI.
• Suppression of Myocardial Ischemia after AMI (1998)
  • Comparison of intensive medical therapy versus PCI on myocardial perfusion imaging (SPECT) 4.5 and 43 days after AMI (in 44 patients).
  • Event-free survival was superior in patients who had a significant reduction in LV perfusion defect size compared to those who did not.
  • Intensive medical therapy and PCI were comparable at suppressing ischemia in stable patients after AMI.
• FRISC II Trial (1999, 2000)
  • 2457 patients with unstable CAD (symptoms of increasing ischemia or occurring at rest or suspected AMI verified by ECG ST segment depression or raised biochemical markers) randomly assigned after 48 hours to invasive or non invasive approach (angiography for a positive exercise test, refractory or severe angina or MI).
  •  There was a significant lower rate of MI in the invasive group at 6 months.
  • There was no significant difference in mortality at 6 months.
  • The mortality benefit with invasive therapy was only seen in patients who had evidence of inflammatory activity at baseline and only in men.
  • The greatest benefit with invasive therapy was seen in high risk patients (ST depression on ECG and/or biochemical markers of myocardial damage).
  • Between the first and second years of follow-ups, there was no further difference in mortality, but there continued to be fewer additional MIs in the invasive group.
• TACTICS-TIMI 18 (2001)
  • 2020 patients presenting with UA or an NSTEMI were randomized to an invasive strategy (catheterization within 4 to 48 hours and revascularization with PCI or CABG if possible) or conservative medical therapy. All patients received tirofiban for 48 to 108 hours.
  •   At six months the rate of death or nonfatal MI was reduced to a similar degree with both approaches.
  • Rehospitalization for an ACS was significantly lower with an invasive strategy.
  • The reduction in primary endpoint with the invasive approach was seen only in patients with elevated serum troponin (> 0.1 mcg/ml). No improvement was noted with the invasive approach in patients with serum troponin I concentration below 0.1 mcg/ml.

Clinical Trials- Early Invasive Approach

• TACTICS:
  •   No ST-segment change (62%): fared worse.
  • Tropinin negative patients (59%): little or no benefit.
  • Taking aspirin: no benefit.
  •   Combined risks (death, MI, rehospitalization) at 6 months = 16%.
• FRISC II
• No ST segment change: death / MI at 6 months higher.
•   Isolated T-wave inversion: no benefit.
• Tropinin negative patients (42%): no significant benefit.

• RITA 3 Trial (2002)
  • 1810 patients with non-ST elevation ACS. Patients were assigned to an early intervention or conservative strategy. All patients were given enoxaparin.
  • Endpoints were combined rate of death, nonfatal MI or refractory angina at 4 months; and combined rate of death or nonfatal MI at 1 year.
  • At 4 months and at 1 year and 2 years, rates of death or MI were similar in both treatment groups.
  • There was a lower rate of refractory angina in the invasive group after 4 month and one year compared to medical group.
• CAPTIM Trial (2002)
• Primary angiography versus prehospital fibirnolysis in AMI.
• 840 patients presenting with acute MI and ST-segment elevation. Patients were assigned to prehospital fibirnolysis with accelerated alteplase or primary angioplasty.
• Primary endpoint was composite of death, non fatal reinfarction and non-fatal disabling stroke at 30 days.
• Median delay between onset of symptoms and treatment was 130 minutes in the prehospital-fibrinolysis group and 190 minutes (time to first balloon inflation) in the primary-angioplasty group.
• Mortality rates did not differ significantly between two groups.
• There was a trend towards more stroke and more recurrent infarction in the prehospital fibrinolysis group.
•  ICTUS Trial (2004)
  • The goal was to evaluate the use of an early invasive strategy compared with a more conservative, selective invasive strategy in troponin positive patients with non-ST elevation ACS.
  • Patients with unstable angina who were troponin positive, 604 were randomized to early coronary angiography within 24-48 hours and PCI within 48 hours or CABG as soon as possible. 597 patients received intensive medical treatment including ASA, enoxaparin, beta-blockers, nitrates, clopidogrel and high-dose statin therapy. Angiography and intervention were only done in case of refractory angina or ischemia on pre-discharge exercise testing.
  • There was no difference by treatment group in the primary composite endpoint of death, MI or rehospitalization for ACS at 6 months.
  • MI rates were higher in the early invasive group, but there was no difference in mortality at 6 months.
  • A large percentage of patients (47%) in the conservative strategy underwent early revascularization.

References and Suggested Readings

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