Terawan Agus Putranto has been known quite some time as a controversial figure in medical field of interventional radiology. He has been known to use on a regular basis intra-arterial heparin flushing procedure he claims as a therapeutic method to clean brain arterial clog or blockage which causes ischemic stroke, he even uses the procedure for alleged prevention of stroke although it has not been proven scientifically.1 It is widely a popular procedure for people who are terrified against the prospect of having stroke attack, including one of ministers in Yudhoyono administration who once published his personal experience of having his “brain sewerage” dirt cleaned off in his personal website.2 Patient list is long to have his service in Gatot Subroto Central Army Hospital where he works every day. He is reported to clean 30-40 patient brains every day, an impressive number, costing 30-40 million Rupiah for each patient.3

Much to my surprise, this controversy did not prevent him to be one of presidential doctors4 who are responsible to take care of the president wellbeing. It did not make him barred from practicing this unproven therapeutic procedure. I do not know why Indonesia Medical Council did not do anything to prevent this?

Now He has taken it to a next level. Trying to prove it scientifically by conducting research to obtain his doctoral degree in the Faculty of Medicine University of Hasanuddin, the very institution where I work as a lecturer. This step may be appreciated; however it also proves that he had been using a shoddy treatment without scientific prove which is unethical and unlawful to say the least. Well, I am not going to fuss further in this matter. I am more interested in how he and his team prove scientifically that his procedure is really worth what he claimed.

I only found one publication about his procedure which can be accessed publicly. 5 It is in an Indonesian open access journal called Bali Medical Journal. Based on his thesis title “EFEK INTRA ARTERIAL HEPARIN FLUSHING TERHADAP REGIONAL CEREBRAL BLOOD FLOW, MOTOR EVOKED POTENTIALS, DAN FUNGSI MOTORIK PADA PASIEN DENGAN STROKE ISKEMIK KRONIS”, Dr. Terawan measured IAHF effects on three dependent variables namely regional blood flow, motor evoked potentials, and motoric functions in chronic ischemic patients.

In the published report, he and his team only published on improvement of motoric function by using Manual Muscle Test-Medical Research Counsel Score. So we need to wait for more published data on regional blood flow, and motor evoked potentials as dependent variables. However, one can safely assume that study design in this study is the one described in the published report. So no need to wait the other data to comment on the study design and methodology used in the study.

Is there a place for reperfusion therapy for chronic ischemic stroke?

It is obviously clear that Terawan and his team intended the paper to show that heparin flushing does the magic by cleaning the blockage of brain artery

So they are kind of trying to prove that IAHF is a reperfusion modality for chronic ischemic disease. As far as I am concerned reperfusion using tPA and other thrombolytics are only proven treatment for acute ischemic stroke which are caused by thrombosis or blood clot within 3 hours after the onset. If the golden hours pass, then it is considered less effective or may be wasting of time and money and may increase intracerebral haemorrhage or bleeding.6 Tissue Plasminogen Activator has been used for so long and proven to be efficacious in acute ischemic stroke since 1990s after extensive trials.7 There is not any study addressing reperfusion using thrombolytics for chronic ischemic stroke. So using IAHF as a therapy before rigorous trial is misconduct and irresponsible to say the least. Terawan had been doing that before trial.

Subjects of Study

The study included patients diagnosed with chronic ischemic stroke both by radiology and neurology examination. There are no clear cut subject criterias used. Instead he may have pooled all patients with the diagnosis together irrespective of the potential diversity of the patients in terms of clinical severity, severity or extension of infarct lesions in the brain, underlying mechanisms of ischemic stroke. These subjects’ criteria will obviously pose a threat to the validity of subjects included in the study. It is widely known that infarct volume either in acute or chronic ischemic is determinant of survival of subjects. The team did not mention what criteria on ischemic stroke subjects to be considered chronic in terms of length time after the onset. Is it more than 25 days after the onset? More than one year? Or more than 5 year after the onset of acute ischemic stroke? The longer the period after the onset of stroke attack it is likely milder ischemic stroke when it is in acute phase. The longer the period from acute episode, more likely that collateral natural reperfusion into ischemic area of the brain has occurred, so no need reperfusion therapy of any kind.

Is it really a randomized controlled trial?

In the paper they say the design of the study is “pretest-posttest group design, with randomized controlled trial”. There is no pretest-posttest RCT. In true RCT, subjects with comparable criteria or condition are randomized into at least two groups i.e. one the control group and the other is the intervention group of interest. The intervention group can be more than one if it is necessary to test many interventions, drugs, or new protocols of therapy. The group of interest outcomes after intervention is compared to control in terms of efficacy, safety, and other variable. There is no definitely pretest-posttest in RCT. In pretest-posttest design, subjects of study are also the control of the study. This is not considered a true clinical trial.

It is obvious from the report the design of the study is one group, pretest-posttest. Let us look at the experimental study using pretest-posttest designs which I downloaded from www.dartmouth.edu/~oir/docs/Types_of_Experimental_Designs_Handout.doc

2 Group, Post-test Comparison

Treatment Post-test X O O

The main advantage of this design is randomization. The post-test comparison with randomized subjects controls for the main effects of history, maturation, and pre-testing; because no pre-test is used there can be no interaction effect of pre-test and X. Another advantage of this design is that it can be extended to include more than two groups if necessary.

One group Pre-test, Post-test

Pre-test Treatment Post-test O X O

Minimal Control. There is somewhat more structure, there is a single selected group under observation, with a careful measurement being done before applying the experimental treatment and then measuring after. This design has minimal internal validity, controlling only for selection of subject and experimental mortality. It has no external validity.

Two groups, Nonrandom Selection, Pre-test, Post-test

Group Pre-test Treatment Post-test Experimental group = E O X O Control Group = C O O

The main weakness of this research design is the internal validity is questioned from the interaction between such variables as selection and maturation or selection and testing. In the absence of randomization, the possibility always exists that some critical difference, not reflected in the pretest, is operating to contaminate the posttest data. For example, if the experimental group consists of volunteers, they may be more highly motivated, or if they happen to have a different experience background that affects how they interact with the experimental treatment – such factors rather than X by itself, may account for the differences.





Two groups, Random Selection, Pre-test, Post-test

Group Pre-test Treatment Post-test Experimental group = E (R) O X O Control Group = C (R) O O

The advantage here is the randomization, so that any differences that appear in the posttest should be the result of the experimental variable rather than possible difference between the two groups to start with. This is the classical type of experimental design and has good internal validity. The external validity or generalizability of the study is limited by the possible effect of pre-testing. The Solomon Four-Group Design accounts for this.

Solomon Four-Group Design

Group Pre-test Treatment Post-test Pre-tested Experimental Group = E (R) O X O Pre-tested Control Group = C (R) O O Unpre-tested Experimental Group = UE (R) X O Unpre-tested Control Group = UC (R) O

This design overcomes the external validity weakness in the above design caused when pre-testing affect the subjects in such a way that they become sensitized to the experimental variable and they respond differently than the unpre-tested subjects.

So it is obvious, Terawan study has no external validity and minimal internal validity. To claim the study as a an RCT is outright false. At least they should have tried the two groups, random selection, pretest-posttest design in order to have more powerful study design although it is not an RCT itself. Minimal validity means that the study design is to large extent biased, no external validity means that the study result can not be generalized to population. So the study result can not be used as a prove to validate the use of IAHF to treat chronic ischemic stroke not to mention to claim that it can prevent stroke attack.

Terawan’s IAHF procedure is also popular method he uses to allegedly prevent stroke in patients who have a range of symptoms they believed to have related to the clogging of their brain. Symptoms such as vertigo, dizziness, headache, any perceived weakness of extremities, other non specific symptoms, even allegedly healthy people who only need to make sure their brain artery healthy are welcomed to undergo the procedure.

4. How did they measure the MMT?

In the article they did not say anything about which muscles they checked. Upper limbs? Lower limbs? How did they come up with the mean score 30.21 +/- and 36.27+/-11.59 (they actually used comma to designate decimal which ok in Bahasa Indonesia, but actually we have to use point (.) instead in english, not a good job from the journal editing section). Did they add up the score of four limbs for each patients?

How many trained physician and neurologist involved in rating the MMT? Are they all comparatively skillful? How much is the inter-rater reliability? Due to non blinded nature of MMT assessment in the study (the examiner knew which patients have and have not received the IAHF) the result was prone to bias (observer bias), and can be easily geared to support the study hypothesis. That is why double blind RCT is often used design to prevent this kind of bias and other study biases.

5. Statistical method used proper?

MMT Score is ordinal data, so to compute the difference using parametric T Test is little bit improper, better to use non parametric such as Wilcoxon rank test.

In conclusion, the study report of IAHF shows it is not a randomised controlled trial (RCT) which is the golden standard of assessing efficacy of new drugs or new methods, which makes the result falls short to justify IAHF procedure as a therapeutic approach not to mention as a preventive measure against stroke.

Suggestion:

To resolve this controversy, I humbly suggest to perform multi-center double blind randomized controlled trial which hopefully will involve many well-known university associated hospitals and national referral hospitals as well as reputed experts with different specializations, medical ethics, biostatistics, etc . Of course this will need massive funding and well designed preparation. The question is how many clinical experts available who are able to perform IAHF procedure? Interventional neurologists who have the skill to run DSA may be involved if interventional radiologists are not sufficient.

Reference