Results of Clinical Trials

M. MOHSEN IBRAHIM, MD
Prof. of Cardiology- Cairo University
President of the Egyptian Hypertension Society

·         Factors Influencing Results of Clinical Trials

·         Limitations Of Clinical Trials

FACTORS INFLUENCING RESULTS OF CLINICAL TRIALS

-        Comparison of the efficacy of therapeutic approaches, which policy (pharmacologic or intervention) is based upon data from large randomized controlled clinical trials .

-            Results of clinical trials will depend upon:

1.   Endpoints selected.

-     Type of endpoints, primary or secondary, soft surrogate or hard, whether results are those of single endpoint or composite (the sum of the results of a number of endpoints). Common composite endpoints are all cause mortality, fatal and non-fatal myocardial infraction, and refractory angina requiring urgent revascularization.

-          Examples of endpoints:

·         Soft

-          Relief of anginal pains.

-          Increased in exercise capacity.

·         Surrogate

-          Improvement in stress ECG.

-          Decrease in perfusion defect in nuclear perfusion imaging.

-          Changes in carotid intimal medial thickness (carotid Duplex ultrasound).

-          Regression of atherosclerotic plaque in intracoronary ultrasound (IVUS).

-          Decrease in inflammatory markers e.g. hs CRP.

·         Hard

-          Total and cardiac mortality.

-          Myocardial infarction.

-          Need for urgent revascularization (PCI or CABG).

-          Heart failure.

-          Stroke.

2.   Duration of follow-up period

-       Period of observation for development of endpoints varies from days to years. Some studies evaluated the effects of therapy over two weeks, others over five years. Long term results of therapy may be different from short term outcomes. In many trials early differences favouring one approach disappears during a longer period of follow-up.

3.  Patient population

-         Results of therapeutic intervention can differ depending upon gender (males versus females), age (young versus elderly) and the risk profile of patients which includes severity of angina, extent and severity of CAD, presence of ST-segment changes, elevated markers of myocardial necrosis (e.g. troponin), associated cardiovascular risk factors (e.g. diabetes, dylipidemia, hypertension), and left ventricular dysfunction.

Limitations of Clinical Trials

·                      Type of Patient Population

Patient population in clinical trials sometimes does not represent the patient population seen in routine every day practice. There is usually a list of exclusion criteria in clinical trials which makes the results inapplicable to the average patient population. Furthermore, the number of patients entered into trials was only a small percentage of the number screened and are therefore not reflective of the general population.

Patients included in randomized trials were highly selected. Thus, generalizability of results from the studies to the general population of patients with CAD may be limited.

·                     Availability of Resources and Expertise

Coronary interventions (PCI and CABG) done in clinical trials are usually performed by experienced and trained physicians in well equipped hospital laboratories. These facilities are not always available in the majority of hospitals particularly in third world countries, which makes the results difficult to reproduce.

An important question is whether the results from controlled clinical trials at major centers can be applied to community practice.

·                     Choice of Endpoints

Endpoints of first choice in assessment of therapeutic efficacy are hard endpoints of total cardiovascular mortality and development of myocardial infarction. Addition of softer endpoints (angina, ischemia) to the previous hard ones may make a significant difference favouring one therapeutic approach over the other. Therefore, the results of clinical trials should be evaluated and interpreted based upon the type of endpoints. Addition or inclusion of soft endpoints may limit or enhance differences between different therapies.