You are a Health Operations Coordinator in one of the government hospitals in your locality. One of your responsibilities is to coordinate pharmacy services along with other hospital services. In your recent meeting with department heads, the chief of the Cardiovascular Section requested that the pharmacy should have stocks of streptokinase. He emphasized that patients who are admitted with symptoms of acute myocardial infarction should immediately be given thrombolytic therapy. He went on to discuss that large studies have already proven the beneficial effect of early administration of the drug. You listened to him in earnest and decided to look into the possibility of requesting streptokinase. However, you are faced with bigger problems should you even consider the request: 1) you have to determine if the evidence really points to longer survival, 2) you have to assess if the data is applicable to patients admitted in your hospital or if you can generalize the results to the local setting, 3) you have to evaluate the efficiency of treatment in the local setting and in the hospital environment and, to top it all, 4) you have to gather the above-mentioned information accurately and sufficiently in order to present it to the board with the purpose of convincing them.
You pose the question, ‘in a patient with suspected MI, does treatment with streptokinase improve survival?’ Your task then is to utilize the Section Chief as your first resource. You immediately ask his assistance on retrieving an article and he was able to give you a full text copy of ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomized comparison of intravenous streptokinase, oral aspirin, both or neither . He showed you how he retrieved this by using the Cochrane Library utilizing the key words “Streptokinase [Mesh] AND Infarction [Mesh]”.
Read the article and decide:
- Is the evidence from this randomized trial valid?
- If valid, is this evidence important?
- If valid and important, can you apply this evidence in caring for patients?
You can only accomplish this by applying certain guides which are summarized in the following table. You then assess the article according to these guides and decide if it is useful.
Completed Therapy Worksheet for EBM in Developing Countries
Citation
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii:349-360.
Appraising an Article on Claims of Effectiveness
Are the results valid?
- Was the assignment of patients to treatments randomized?
- YES. See p. 349, title and under Summary, “17187 were randomized with placebo control…” Details are in p. 350, under Randomisation.
- Was follow-up adequate?
- YES. See p. 351, under Follow-up, “the completeness of follow-up is 99% to discharge, 97% to week 5.”
- Were patients analyzed in the groups to which they were randomized?
- YES. See p. 350, under Randomisation, “whether or not the treatment in the pack was actually given, patients remained in their originally allocated group for an ‘intention-to-treat’ analysis.”
- Were the patients, health workers, and study personnel blind to treatment?
- YES. See p. 350, under Treatment, “half of the patients were allocated randomly to receive streptokinase and half to receive matching placebo.”
- Were the groups similar at the start of the trial?
- YES. See p. 352, under Results, “this large size ensured good balance between the treatment groups for the main pre-randomization features that were measured and should do likewise for those that were not.”
- Aside from the experimental intervention, were the groups treated equally?
- YES. See p. 350, under Treatment, “in all other respects, physicians were free to use whatever additional therapy they considered necessary.”
What are the results?
- How large was the treatment effect?
- See p. 352, Results. See p. 355, figure 2.
| Outcome | Streptokinase | Placebo | RR | RRR | ARR | NNT |
|---|---|---|---|---|---|---|
| Vascular Mortality | $$text{EER}= 791/8592\\text{EER}= 9.2%$$ | $$text{CER} = 1029/8595\\text{CER} = 12.0%$$ | $$0.77 (77%)$$ | $$0.23 (23%)$$ | $$0.028 (2.8%)$$ | $$36$$ |
- How precise was the estimate of treatment effect?
- Vascular Deaths
$$0.77~[95%~ text{CI} ~(0.70, ~0.84)]$$
Will the results help me in caring for my patients?
- Can the results be applied to my patient care?
- See Applicability Worksheet.
- Were all clinically important outcomes considered?
- YES
- Are the likely treatment benefits worth the potential harms and costs?
- See Applicability Worksheet.
Completed Therapy Applicability Worksheet for EBM in Developing Countries
Citation
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2.
Lancet 1988; ii:349-360.
Deciding on the Applicability of Clinical Trial Results
Biologic
- Are there pathophysiologic differences in the illness under study that may lead to a diminshed treatment response?
- NO. Local studies indicate similar pathologic changes, risk factors and disease pathogenesis between North Americans and Filipinos.
- Are there patient differences that may diminish treatment response?
- NO. Although there are no local pharmacokinetic studies, post-marketing surveys show that the incidence of major bleeding is similar. This suggests that Filipinos are no different from North Americans in terms of treatment response.
Social and Economic
- Are there important differences in patient compliance that may diminish the treatment response?
- NO. Since streptokinase is given intravenously in a single dose for in-hospital patients with MI, compliance is not an expected problem.
- Are there important differences in provider compliance that may diminish the treatment response?
- YES. Lack of an efficient blood banking system may hinder our ability to cope with episodes of major bleeding.
Epidemiologi
- Do my patients have comorbid conditions that significantly alter the potential benefits and risks of the treatment?
- YES. Since death from sepsis is a relatively common cause of death in our hospital accounting for 10.4% mortality. The impact of streptokinase on overall mortality may be less than expected. A better measure may be cardiac death.
- Are there important differences in untreated patients’ risk of adverse outcomes that might alter the efficiency of treatment?
- YES. The cardiac death rate in ISIP is 10%. See computation below.
Using the local, unpublished cohort study entitled, Acute Myocardial Infarction in Tertiary Centers in Metro Manila (ISIP Study), you estimate the treatment benefit among Filipinos with acute myocardial infarction from streptokinase.
- Overall baseline risk for in-hospital cardiac mortality among Filipinos: 10%
(crude cardiac mortality derived from ISIP) - The relative risk reduction from vascular deaths in ISIS-2: 23%
The relative risk from vascular deaths is: 77%
From the above data, you derived the absolute risk reduction and NNT for the local cohort.
$$
quad text{EER} = text{RR}times text{CER} \
quad text{EER} = 0.77 times 10% \
quad text{EER} = 7.7%
$$
$$
quad text{ARR} = 10% – 7.7% \
quad text{AAR} = 2.3%
$$
$$
quad text{NNT} = 1/0.023 \
quad text{NNT} = 43 \
$$
For presentation purposes you developed a CAT on therapy. This one-pager, easy reference will be able to present all major points and help guide you through your discussion.
MI-streptokinase saves lives
Clinical Bottom Line
Streptokinase improves survival in patients with MI. Cost of treatment is a major issue for Filipinos. Patients should be involved in the decision.
Citation
ISIS-2 Collaborative Group. ISIS-2.
Lancet 1988; ii:349-360.
Clinical Question
Among Filipino patients with suspected MI, will administration of streptokinase decrease in-hospital mortality?
Search Terms
‘streptokinase’ [MESH] and ‘myocardial infarction’ [MESH] and ‘mortality’ [MESH] from Cochrane Library
The Study
- Double-blinded concealed randomised controlled trial with intention-to-treat.
- The Study Patients: 17187 patients with suspected AMI
- Control group (N = 8595): matching placebo infusion
- Experimental group (N = 8592): 1.5 million units of streptokinase infused for 1 hour
The Evidence
| Outcome | Time to Outcome | CER | EER | RRR | ARR | NNT |
|---|---|---|---|---|---|---|
| Vascular Deaths | $$0.120$$ | $$0.092 | $$23%$$ | $$0.028$$ | $$36$$ | |
| $$95% Confidence Intervals$$ | $$16%~text{to}~31%$$ | $$0.019~text{to}~0.037$$ | $$27~text{to}~53$$ |
Comments
- Early survival advantage and persists for several years.
Summary
- You determined that the trial is valid and you were able to look into the results of the trial by applying the guides on therapeutic effectiveness.
- You were able to demonstrate by using the guides on applicability that evidences derived from foreign trials can be applied to the local setting without the need for repeating the RCT.
- From the whole process, you were able to determine the importance of the evidence and more significantly, appreciate its application in clinical practice.
- The data you gathered can now be used in convincing the hospital board on the effectiveness of streptokinase in decreasing in-hospital mortality. Efficiency of treatment, of course, is dependent on a number of factors that should be considered.
- Overall, the method not only reinforced clinical decision making, but placed emphasis on its value in making hospital-wide decisions.
References
- Baigent C, Collins R, Appleby P, et. al. ISIS-2: 10 year survival among patients with suspected myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both or neither. BMJ 1998; 316:1337-1343.
- Dans AL, Dans LF, Guyatt GH, Richardson S for the Evidence-Based Medicine Working Group. User’s Guides to the Medical Literature. XIV. How to Decide on the Applicability of Clinical Trial Results to Your Patient. JAMA 1998;279(7):545-549.
- Guyatt GH, Sackett DL, Cook DJ, for the Evidence-Based Medicine Working Group. User’s Guides to the Medical Literature. II. How to Use an Article About Therapy or Prevention. A. Are the Results of the Study Valid? JAMA 1993; 270(21):2598-2601.
- Guyatt GH, Sackett DL, Cook DJ for the Evidence-Based Medicine Working Group. User’s Guide to the Medical Literature. II. How to Use an Article About Therapy or Prevention. B. What Were the Results and Will They Help Me in Caring for My Patients? JAMA 1994; 271(1):59-63.
- ISIP Study Group. Acute Myocardial Infarction in Tertiary Centers in Metro Manila: In-Hospital Survival and Physicians’ Practices. Unpublished data, 1996.
