M
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Volume 1 December

ED

2015

-The Informed Prescriber

N3

HECK

o

Anti-HCV agent LDV/SOF combination
8 week treatment may be better to reduce harm and costs with same efficacy

Is Alteplase Beneficial for Treating
Ischemic Stroke?
CONTENTS （December 2015,Vol. 1, No. 3）

Editorial:“Surrogate endpoint” qualify “real advance”?

34

New Products
Anti-HCV agent LDV/SOF combination (brand name: Harvoni)35

8 week treatment may be better to reduce harm and costs with same efficacy

Febuxostat (brand name: Febric): Inferior to allopurinol

38

Too frequent cardiovascular events, gouty attacks, serious allergy

Review
Is Alteplase Beneficial for Treating Ischemic Stroke?
No proven efficacy if it is given 1.5 hours after onset

40

MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3 ・ Page 33

M
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ED

-The Informed Prescriber

HECK

Editorial“Surrogate endpoint” qualify “real advance”?
Translated from the editorial in Med Check-TIP (in Japanese) 2015; 15 (Nov:#61); 102.

Surrogate endpoints are overused.

For these reasons, even though the drug shows

The case of febuxostat (brand name: Feburic)remarkable effectiveness as measured by theprovides a typical example. Although the primary

surrogate endpoint, there remain significant

purpose of the drug should be prevention of

doubts as to whether it can improve long-term

the severe pain that accompanies an acute gout

overall prognosis.

attack, the endpoint used in clinical trials was

In addition, the drug is very expensive. If it

reduction of the serum uric acid level to 6.0mg/dL.

were to be used to treat all HCV-infected persons

Febuxistat was approved because it achieved thisin Japan, the total cost would be equivalentsurrogate endpoint, even though the incidence ofto the total amount of money spent annuallyacute gout attack was higher in the group treatedon pharmaceuticals in Japan. Considering thewith febuxostat than in either the placebo group

uncertainty of long-term prognosis and its highor the group treated with the standard drugcost, this drug can in no way be called “ realallopurinol.

advance” . In issue No. 60 of “ Med Check TIP” ,Similarly, in clinical trials of the anti-HCV drug

we prematurely used the phrase “ real advance”

combination ledipasvir-sofosbuvir (brand name:in describing sofosbuvir. We now change our

Harvoni), a surrogate endpoint of “ sustained

evaluation of sofosbuvir to “ for severely

virological response (SVR)” was used. In trials

restricted use” .

of the drug that used neither a placebo nor aAmong new drugs developed since 1990, anti-HIV

standard drug as a control, 99% of participants

drugs are truly “ real therapeutic advance” .

achieved the surrogate endpoint. Since, in the

The decrease of CD4 positive lymphocytes (helper

natural state, the SVR rate is extremely low,

T-cells) was an excellent surrogate endpoint thata result of SVR12 (SVR for 12 weeks or more)correlated well with the development of AIDS orindicates that a virus-negative state will likely

death due to AIDS. Even so, randomized control

continue for the long term, and strongly suggests

trials (RCTs) using placebos were conducted. In thethat the drug prevents HCV-caused liver damage.

first RCT, conducted on 282 patients with AIDS or

Nevertheless, a surrogate endpoint is still a

AIDS-related complex (ARC, or “ pre-AIDS state” ),surrogate endpoint. There is no guarantee that

27 patients from the placebo group and 1 patientanti-HCV drugs can increase life expectancy.

from the zidovudine group died over an 8- to

One reason for uncertainty about the long-

24-week period. The RCTs confirmed that the drugs

term efficacy and safety of the drug is thatwere effective in suppressing the development ofledipasvir is strongly suspected to be more toxic

ARC into AIDS and in dramatically reducing thethan sofosbuvir. Toxicities that can be surmisedmortality rate.

to cause infection and/or general debilitation

As anti-HIV drugs have strong toxicities,

were observed with ledipasvir at the dose said to

additional RCTs were required to determine

be safe by the manufacturer of the drug, and inwhether the drugs were appropriate for long-termclinical trials of ledipasvir in which the treatment

use with mildly-ill patients.

period was extended, infections and bone fractures

In conclusion, in order to be able to say that

related to general debilitation were observed.

the anti-HCV drug discussed above is truly “ realMoreover, although the medication used clinicallyadvance” , RCTs that demonstrate improvement of

is a combination drug, no toxicity studies of thelong-term prognosis are needed.

combination drug have been conducted.
Page 34 ・ MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3

New
New Products
Products
Anti-HCV agent LDV/SOF combination(brand name: Harvoni)
Eight-week treatment may be better to reduce harm and costs with same efficacy
Translated synopsis based on Med Check TIP (in Japanese) 2015; 15 (Sep:#61); 103-108.
General description:
This anti-HCV combination drug containing ledipasvir(LDV) and sofosbuvir (SOF) (L/S combination: brand name
“Harvoni”) was approved for "improvement of viremia inchronic hepatitis or compensated cirrhosis induced byserotype (or genotype)-1 hepatitis C virus” in August 2015
in Japan. Type 1b hepatitis C is the major hepatitis C virus
in Japan. Sofosbuvir is an NS5B polymerase inhibitor andledipasvir is an NS5A replication complex inhibitor (Figure 1).

Efficacy:
The multivariate logistic regression analysis was conductedusing the (non-controlled) clinical trials data from theJapanese regulatory documents. Predicted percentage ofsustained virological response for 12 weeks or longer after
the end of the treatment (SVR12) in Japanese trials was 99.1
% among the patients with hepatitis C serogroup 1 (genotype
1) (Table 1a and 1b). SVR12 in patients with genotype
1b tended to be higher than in those with genotype 1a(p=0.0758) in the US (Table 1a).

Figure 1: HCV genome and the mechanisms of action of anti-HCV agentsThis figure was reconstituted from ref. [5] and [6], by the MedCheckTIP editorial team
Efficacy and safety of different treatment durations:
While treatment for 24 weeks gained significantly higher
SVR12 than treatment for 12 weeks or 8 weeks, serious
systemic adverse events such as infections and fractures
were observed 7 to 25 times more frequently with 24 weeks
treatment than 12 weeks treatment (Table 2). There wasno additional beneficial effect in 12 weeks treatment whencompared with 8 weeks treatment (Table 1b).

SVR12 observed in Japan tended to be apparently higher
than that in the US. However, lower average body weightand higher proportion of patients with genotype 1b among
Japanese may contribute to this difference. Hence data fromthe US for higher frequency of serious events in 24 weeks
treatment and no difference in efficacy between 12 weeks and8 weeks treatment could also be applied to Japanese cases.

MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3 ・ Page 35

New Products
Table 1: Results from the clinical trials in Japan:

Proportion of patients with genotype 1b is 96 to 97 % among all genotype 1 hepatitis C patients.
All patients have chronic hepatitis C infection or compensated liver cirrhosis due to hepatitis C in Japan.
Duration of treatment is 12 weeks for all patients.
* a: L/S: ledipasvir/sofosbuvir combination, L/S+R: L/S + ribavirin* b: SVR12: sustained virological response for 12 weeks or longer* c: Predicted value: predicted value (% ) and 95% confidence interval (95% CI) by exploring the resultsby the multivariate logistic-regression analysis including Japan and U.S. studies* d: Predicted value for the “total” is a value using the data of the studies for 12 weeks and 8 weeks.

Table 1-b: SVR12 from various clinical trials of LDV/SOF combination

Resistance:
L31 and Y93H variants were mainly associated with noresponse. Table 3 shows that odds of resistant associatedvariants (RAV) among patients with no response was 30 to
54 times higher compared with baseline odds of RAV for
genotype 1b (p<0.001) and 5 to 17 for genotype 1a (p<0.01).
Toxicity:
We found serious flaw in the toxicity studies of the LDV/SOF combination. The dose-limiting toxicities and the target
organ/tissue were not determined for ledipasvir alone.
Moreover, the harmful dose in which death, infections
and general deterioration that were also observed in theclinical trials (in 24 weeks treatment) were considered
as non-observable adverse effect level (NOAEL) by thepharmaceutical company and regulator. Combination of LDVand SOF was not tested in the toxicity studies for approval,even though they are always used in combination in theclinical setting.

* a: Proportion of patients with genotype 1b is 96-97% among all genotype 1 hepatitis C
patients in Japan. Hence all patients with gentype 1 in Japan were consideredgenotype 1b for multivariate logistic regression analysis.
* b: CH: chronic hepatitis, LC: compensated liver cirrhosis
CH/LC: chronic hepatitis or compensated liver cirrhosis*c: L/S: ledipasvir/sofosbuvir combination, L/S+R: L/S + ribavirin*d: naïve/not: first time treatment / history of treatment*e: number of subjects*f: SVR12: sustained virological response for 12 weeks or longer*g: Predicted value: predicted value (% ) and 95% confidence interval (95% CI)
by exploring the results by the multivariate logistic-regression analysis
including Japan and U.S. studies

Page 36 ・ MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3

Conclusions and recommendations:
LDV/SOF combination medication improves viremia
remarkably but not by 100 % . We do not recommend theuse of the drug to the patients with sustained normal level of
ALT. Even in the case with abnormal ALT values, efficacy on
SVR12 is not different with treatment duration (12 weeks vs
8 weeks).
Because the toxicities are duration-dependent and nonspecific with infection or systemic debilitation, we recommend
to use the least effective duration (8 weeks) unless patients
have resistance asso ciated variant. We recommend
examination of RAV for L31 and Y93H which are related to
no response. Twelve weeks treatment should be indicated inonly those who have positive RAV. Eight weeks treatment may
be preferable for the others.

Table 2: Comparison of serious adverse events by treatment duration

SAE: serious adverse event
Odds ratio=25.5 (95% CI: 4.1, 1054, p<0.0001) (meta-analysis excluding trial 0108).
Odds ratio=7.1 (95% CI: 2.9, 17.5, p<0.0001) (using total).

Table 3: Resistance associated variants (RAV) related to “no response”

Denominators (N) at the baseline were all the patients tested.
For the non-responded cases, denominators (N) were also all non-responders.
“No RAV” was observed in one among 8 genotype 1b patients and 7 among 29 genotype 1a patients with no response.
Odds ratios (the odds of RAV among patients without response by the baseline odds) were calculated.
If it is significantly higher, the RAV may be related to ineffectiveness.

Principles of Toxicity study by Zbinden G (F. Hoffmamn-La Roche & Co)“In any toxicity experiment, animals are treated with drugs andobserved for toxic manifestations. In order to increase the chancesof recognizing possible toxic properties, the dose is raised above
the therapeutically useful range, the duration of treatment is often
lengthened, and the drug is administered not only to one individual
animal but to animal groups. Thus, the toxicity experimenttries to imitate the clinical use of the drug and although boldexaggerations with respect to dose and duration of treatment arecommon and permissible, it is important that the future therapeutic
applications in man guide the planning of a toxicity study.”

References
1) Med Check TIP team, Sofosbuvir. Med Check TIP 2015: 15(60): 75-79.
2) Documents for the approval of Harvoni combination tablet: a)Summary Basis ofApproval (SBA), b)Examination Results by PMDA, c)Package Insert, d)Interview form
3) Press release by Gilliad Science (Aug 31 2015) http://www.gilead.co.jp/
4) Kan-en. jp（www.kanen.jp/）
5) National Institute of Infectious Diseases, Structure and function of HCV genome (inJapanese)
http://www.nih.go.jp/niid/ja/hcv-senmon/624-genome.html
6) Okayama University, Department of Tumor Virology
http://www.okayama-u.ac.jp/user/med/dmb/research-HCV.html
7) Zbinden G. Experimental and Clinical Aspects of Drug Toxicity. Advances in

Based on these principles, toxicity studies of the L/S
combination have many flaws:(1) Dose limiting toxicity and its target organ/tissues of LDV
alone are not determined(2) The major toxicity of LDV may be infections due tosystemic debilitation?
(3) L/S combination was not tested for toxicity at all(4) Other findings: hypoalubuminemia and high cholesterollevel accompanied with increased body weight, and evendeath were not considered as toxicity findings.

Pharmacology 1963：2 (C) , pp. 1-112
8) Documents for the approval of Sofosbuvir:a)Summary Basis of Approval (SBA), b)Examination Results by PMDA
9) Hama, R. Is the revised indication of Interferon rational? TIP “The Informed
Prescriber” 2001: 16(9): 90-97.
10) Med Check TIP team, H.pylori eradication may shorten life span Med Check TIP in
English 2015: 1 (1): 7-9.
11) Medical Expenditure 2014 (released on Sept 3 2015)
http://www.mhlw.go.jp/bunya/iryouhoken/database/zenpan/iryou_doukou_b.html
12) Hama R, Sakaguchi K, Report on the International Comparison of Drug Price-2010(In Japanese): https://hodanren.doc-net.or.jp/news/tyousa/111219yakka2.pdf13) Mizokami M, Yokosuka O et al Ledipasvir and sofosbuvir fixed-dose combination
with and without ribavirin for 12 weeks in treatment-naive and previously treatedJapanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial.
Lancet Infect Dis. 2015 Jun;15(6): 645-53.

MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3 ・ Page 37

New Products

Febuxostat (brand name: Febric)
Too frequent cardiovascular events, gouty attacks, serious allergy:
Inferior to allopurinol
Translated synopsis based on Med Check TIP (in Japanese) 2015; 15 (Sep:#61); 109-113

trials conducted before approval (Table 1).

Synopsis● For the management of hyperuricemia, the first choice is

non-pharmacological intervention such as enough intake ofwater and alkalinisation of urine with least medicine. When it
is failed or not indicated, pharmacotherapy is provided. The
first-line medicine is allopurinol, but itself may induce gouty
attack and serious allergic reactions relatively frequently.
● The

primary aim of the pharmacotherapy for
hyperuricaemia is “reduction and prevention of gouty attackand subsequent complications".
● However, febuxostat was approved only by surrogate● The analysis results of post-marketing adverse reaction

reports that US Food and Drug Administration disclosed
shows that reporting odds ratio (ROR) of cardiovascular
reactions for febuxostat were 2-7 times higher than forallopurinol (Table 2:Next pege).
● Similar efficacy in decreasing blood uric acid level was

Figure 1 ： Proportion of gouty attack(whole period, classified by the drug at the time of gouty attack)endpoint namely "lowering plasma level of uric acid" and notby the achievement of the primary aim.
● Febuxostat use may induce gouty attack paradoxicallymore frequently than allopurinol (Figure 1). It may induce
serious allergic reactions (severe drug eruption, liver damage)
more frequently than allopurinol. Therefore, we DO NOT
recommend febuxostat.
● In addition, cardiovascular events were more reported in

the febuxostat group than allopurinol group in the clinical

Table1 ： Proportion and incidence of cardiovascular events by febuxostat dose in the clinical trials *a

N：number of subjects 、E：events、% /p-y：% /person-year*a：cardiovascular adverse events according to the classification of APTC（Anti-Platelet Trialists’ Collabolation（APTC）and non APTC events
Dose-response relation was not significant. This may be caused because the number allocated to placebogroup was too few. If the subjects were 6 times more than the above, and the event occured at the same
frequency, the dose response would be significant.

Page 38 ・ MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3

Table 2 Comparison of post-marketing spontaneous ADR reports (febuxostat vs allopurinol)

achieved with lower dose in the Japanese clinical trials than in
the Western countries. However, higher area under the curve(AUC) of the blood level seems achieved in Japanese than in
the Western people if it is compared between those who wereadministered with the same dose per kg body weight (Figure2). Therefore, febuxostat may be more harmful for people inJapan than in the Western countries. .

References
1) Japanese Society of Gout and Nucleic Acid metabolism. “Guideline for theTreatment of Hyperuricemia and Gout; 2nd Ed” Jan 2010.
2) Braunwald E et al Edd. Harrison’s Principle of Internal Medicine. 15th ed. 2001
The McGraw-Hill Companies Inc.
3) Prescrire team. Febuxostat, hyperuricaemia: risk of gout attacks, PrescrireInternational 2009; 18(100): 63-65
4) Uloric (febuxostat) tablets label – Food and Drug Administraction.

● Febuxostat does not seem to have the cross sensitivity

http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021856s006lbl.pd

with allopurinol. Hence febuxostat may only be indicated asa second choice when allopurinol and probenecid cannot be
used for an allergy. If indicated, it is essential to commence atlowest dose and very gradually and carefully to prevent gouty
attack.

5) Adenuric (febuxostat) tablets product information - European Medicines Agency
h tt p: // ww w. em a .e ur op a. eu /d o c s/ e n_ GB /d o c um en t _l ib ra ry /E PAR __Product_Information/human/000777/WC500021812.pdf#page=3
6) Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit
J, Lademacher C, Joseph-Ridge N. Effects of febuxostat versus allopurinol andplacebo in reducing serum urate in subjects with hyperuricemia and gout:aFigure 2 ： Relation of the body weight-adjusted-dose and AUC ：Difference between in Japan and in the Western countries

28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum.
2008;59(11):1540-8.
7) Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo
WA, Streit J, Joseph-Ridge N. Febuxostat compared with allopurinol in patientswith hyperuricemia and gout. N Engl J Med. 2005;353(23): 2450-61.(FACT 試験 )8) Documents for the approval of Febxostat: a)Summary Basis of Approval (SBA),b)Examination Results by PMDA, c)Package Insert, d)Interview form
9) Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd
E, Lademacher C. The urate-lowering efficacy and safety of febuxostat in thetreatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther.
2010;12(2):R63.
10) Briefing Document - Food and Drug Administration
http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4387b1-02-Takeda.pdf
11) Becker MA, Schumacher HR, MacDonald PA, Lloyd E, Lademacher C.

Clinicalefficacy and safety of successful long term urate lowering with febuxostat orallopurinol in subjects with gout. J Rheumatol. 2009;36(6):1273-82.
12) Schumacher HR Jr, Becker MA, Lloyd E, MacDonald PA, Lademacher C.

Relation of the body weight-adjusted-dose and AUCinf after single dose
Healthy adult male○：people in Japan（N=52）、 ▲：People inWestern countries（N=48）
The slope of regression line by sight is sharp for Japan than forWestern countries. The difference may be 1.7 times higher in Japanesethan the Western countries. Body weight may be 1.4 times lower andthe relative AUC per body may be 2 times or more in Japanese than in
the Western people. 40mg/day for Japanese may be higher than 80
mg/day for the Western people.

Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety
study. Rheumatology (Oxford). 2009;48(2):188-94
13) Rxisk: https://www.rxisk.org/Default.aspx
14) Park JJ, Roudier MP, Soman D, Mokadam NA, Simkin PA.

Prevalence ofbirefringent crystals in cardiac and prostatic tissues, an observational study.

BMJ

Open. 2014 Jul 16;4(7):e005308.
15) Grewal HK, Martinez JR, Espinoza LR. Febuxostat: drug review and update.
.Expert Opin Drug Metab Toxicol. 2014; 10(5): 747-58.

MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3 ・ Page 39

Review
Is Alteplase Beneficial for Treating Ischemic Stroke?
No proven efficacy if it is given 1.5 hours after onset
Translated synopsis based on Med Check TIP (in Japanese) 2015; 15 (Sep:#60); 85-88
Abstract
Alteplase (rt-PA) is generally considered as a specific medicine for the treatment of acute-phase ischemic stroke.
However, in the NINDS study, which justified the use of rt-PA within 3 hours of onset of stroke especially after 1.5
hours, an unacceptable, extreme bias in favor of the rt-PA group was detected. Therefore, it cannot be considered that
benefit outweighs harm when the drug is given later than 1.5 hours after onset.
The editorial team examined the ECASS-III study, which provided the evidence for the use between 3 to 4.5 hours after
onset. Again, we found an extreme bias in favor of the rt-PA group, thus it is hard to conclude that benefit outweighsharm. IST-3 study which is a randomized study but not double-blinded could have an extreme bias in favor of the rtPA group. Consequently a meta-analysis published in 2014 that included IST-3 remains the same bias uncorrected. In
NINDS, in patients treated within 1.5 hours of onset, bias in background variables was limited hence it is suggested that
their symptoms improved and rt-PA may be effective. Except for them, no evidence has proven that rt-PA improved theoutcome of ischemic stroke. Applying the idea of Dr. Archie Cochrane “One should, therefore (…) always assume thata treatment is ineffective unless there is evidence to the contrary” (see page XX), we must conclude that rt-PA is “noteffective” for treating ischemic stroke when given later than 1.5 hours after onset of stroke.
Introduction:
Alteplase (genetic recombinant) (rt-PA) has been used asa thrombolytic agent for acute myocardial infarction. In
1996, it was approved for the treatment of ischemic stroke(cerebral infarction) by the FDA and subsequently in othercountries in Europe and Asia[1]. In Japan, “the improvementof dysfunctions associated with acute-phase ischemic
cerebrovascular disorders (administered within 3 hours ofsymptom onset)” was added to the indications in 2005.
The NINDS study [2, 3] is the randomized controlled trial(RCT) that provided pivotal evidence for the use of rt-PA
within 3 hours of onset of stroke. The result of this study,
however, is fundamentally questionable for the following
reasons [4]: (1) None of the considerable bias in backgroundvariables was adjusted in the outcome analysis. (Althoughno bias was detected in patients treated within 1.5 hours of
onset, an unacceptable bias was noted in the 1.5-3 hours
group: Figure.1); (2) Almost no case of recanalization wasreported; (3) No difference in 1-year mortality was observed,
Table 1: modified Rankin Scale (mRS) *Page 40 ・ MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3

and the causes of death were unusual; (4) The effect of rt-PA
was reversed by the use of antihypertensives.
Later, another RCT (ECASS-III [5]) reported that rt-PA waseffective when given within 3 to 4.5 hours of symptom onset.
On the basis of this single trial, the guidelines in Westerncountries recommended to use rt-PA within 4.5 hours ofsymptom onset in 2009. In 2011, regulatory agencies in
Europe approved the use of rt-PA within 4.5 hours of onset.
In Japan, in February 2013, a change to include a new time
window of 4.5 hours was approved [1], followed by therevision of the guidelines (the second edition) [6].
Regarding the indications of rt-PA, this article summarizes
the evidence for the validity of the conventional “use within 3
hours of onset”. It also examines the evidence for the validityof the extended use within 3 to 4.5 hours of onset. In the
NINDS and ECASS-III trials, the efficacy of rt-PA was assessed
based on the proportion of patients with a favorable outcome(mRS 0-1) at 3 months (see Table 1).

Changes from the conventional indications of rt-PA
Based on the Guidelines for Intravenous Application of rtPA, the Second Edition published by the Subcommittee on
Revision of the Guidelines for Intravenous Application, theCommittee on Stroke Care Improvement and Social Insurance,
the Japan Stroke Society (hereinafter referred to as “therevised guidelines”), the major differences in the indications of
rt-PA between the old and revised guidelines are shown in acomparative table at the end of the reference[6]. The revised
guidelines state “Intravenous alteplase is indicated in patientswith ischemic cerebrovascular disorder that is treatable within
4.5 hours of symptom onset【Level of Evidence Ia, Grade of
Recommendation A】.” The biggest change is that intravenous
rt-PA administered within 3 to 4.5 hours of symptom onset,
which was previously the off-label use, was included in therevised indications.
Following this change, almost all conditions that used to becontraindicated in the old guidelines based on the package
insert are simply listed as “off-label” in the revised guidelines
even though they are still contraindicated in the current
package insert. For instance, administration of rt-PA “within
3 months onset of ischemic stroke” or “in patients receiving
warfarin with PT-INR > 1.7” are still “contraindicated” inthe package insert. However, they are simply “off-label” inthe revised guidelines. The use of rt-PA in patients with“seizure” or “cerebral aneurysm, intracranial tumor, cerebral
arteriovenous malformation, Moyamoya disease (occlusive
disease in circle Willis) are still contraindicated in the package
insert, but are excluded from “contraindication” and included
in “administer carefully” in the revised guidelines.
Moreover, the revised guidelines raised the age for “administer
carefully” from 75-year and older to 81-year and older, andthe NIHSS scores for “administer carefully” from 23 and above
to 26 and above [6]. In any case, the revised guidelines allow
wider use by listing many “contraindications” in the package
insert under “administer carefully” and raising the upper age
limit for the administration.

Note: The NIHSS is a scale to assess severity of stroke
developed by National Institute of Health (NIH) in the US.
Scores are given to 11 categories, and the scores fromeach category are summed up to assess severity. The
total score of 0 indicates the least severe case while 42
indicates the severest. Assessment is made by classifying
the scores into 0-4, 5-9, 10-14, 15-19, 20-24, and 25 (or26) and above. The severest case is indicated as 25 (or26) and above.

Clinical Trials referred in the Guideline
Table 2 on page 4 of the guidelines [6] summarizes
trial designs, the numbers of cases, onset-to-treatment
time, doses, the primary endpoint, and the frequency of
intracranial hemorrhage in the major clinical trials which
the guidelines are based on. In addition, there is another
trial, ATLANTIS-A [7], on the basis of which ATLANTIS-B was
conducted, although it was not included as a reference in theguidelines. The ATLANTIS-A trial involved a population ofpatients treated within 6 hours of onset of stroke, but was

discontinued due to safety concern regarding the use of rt-PA
between 5 and 6 hours after onset [7].
NINDS [2, 3] is the only RCT that claimed the efficacyof rt-PA administered within 3 hours of symptom onset.
Although the validity of its conclusion remains fundamentallyquestionable, many countries in the world recommend theadministration of intravenous rt-PA within 3 hours of onset,
based on the result of this study as important evidence.
However, as mentioned in the introduction, various problems
are found in the study. The guidelines refer to the ECASS,ECASS-II, and ATLANTIS-A studies with patients treated within
6 hours of onset as well as ATLANTIS-B with patients treatedwithin 3 to 5 hours and EPITHET with patients treated within
3 to 6 hours of onset. However, the efficacy of rt-PA has notbeen confirmed in these studies. Among the RCTs conducted
after NINDS, ECASS-III [5, 8] is the only RCT that involved
patients treated within 3 to 4.5 hours of onset and claimed
the efficacy of rt-PA.
The guidelines refer to IST-3 [9] as important evidence forraising the standard age for “administer carefully” to 81-year
and older. However, it is a large-scale open trial (non-placebo
controlled randomized trial), thus the strength of its evidence
is undermined. ECASS III, and the meta-analysis published in2010 and in 2014 are mainly examined below.
ECASS-III (the evidence for rt-PA within 3 to 4.5 hours) and its
problems(1) The frequency of hemorrhagic stroke is 10-fold higher,
but rt-PA is effective?
ECASS-III is the only RCT that involved patients treatedwithin 3 to 4.5 hours of onset. It was conducted with 821
ischemic stroke patients and compared an intravenous rt-PA(0.9 mg/kg) group (418 patients) and a placebo group (403patients). The primary endpoint was the same as the otherstudies: “a proportion of a favorable outcome (a score of 0 or
1 on the modified Rankin scale) at 90 days” (hereinafter thisis the primary endpoint unless especially mentioned). It was
52.4% in the rt-PA group and 45.2% in the placebo group, andthe odds ratio (OR) was 1.34 (95% CI: 1.02-1.76), thus it was
concluded that “rt-PA is effective” [5]. Regarding harm, thefrequency of symptomatic intracranial hemorrhage was 2.4%
in the rt-PA group and 0.2% in the placebo group (OR: 9.85,
95 % CI: 1.26-77.23). This indicates that the risk of bleedingwas 10-fold higher in the rt-PA group, but the mortality at
90 days was 7.7% in the rt-PA group and 8.4% in the placebogroup with no significant difference.
These findings led to the conclusion that intravenous rt-PA
administered within 3 to 4.5 hours of onset increases therisk of bleeding, but improves an outcome with no significant
difference in mortality between the two groups. Many
countries in the world including Japan extended the time
window in the indications to 4.5 hours, referring to this result
as important evidence [6].
(2) The rt-PA group included less cases with a history ofstroke and severe cases
Various problems in background variables were found in
NINDS (Figure.1,[4]). The following figures 2 and Figure 3
summarize the case of ECASS-III.
The average NIHSS score at time of presentation was
significantly lower in the rt-PA group (10.7 points vs 11.6
points, p=0.025). The proportion of severest cases (NIHSS ≧MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3 ・ Page 41

Review
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Figure 1: Serious bias in the baseline severity of the cases treated during 1.5 to 3 hours after the onset of stroke (NINDS) [3]

Patients treated within 1.5 hours after onset were well randomly allocated to t-PA group or placebo group (baseline severity was not
significantly different: NS). However, patients treated between 1.5 and 3 hours after onset were differently allocated significantly. Odds
ratio of patients with least score in t-PA group compared with placebo group was 5.4（95 ％ CI：2.7, 12.6、p=0.00003）。OR in theseverest cases =0.59（0.35,1.00、p=0.0501）

21) was 9.9 % in the placebo group while it was 5.0 % in thert-PA group (OR=0.48: 95 % CI: 0.28-0.82, p=0.007), roughly
a half of that in the placebo group. Furthermore, even agreater difference was detected between the 2 groups when
the proportions of patients with a history of stroke werecompared (7.7 % in the rt-PA group, 14.1 % in the placebogroup, OR=0.50: 95% CI: 0.32-0.79, p=0.003) (Figure. 2).
The reference [10], which describes the need to reexamine
the efficacy of rt-PA, also criticizes this difference inbackground variables.
(3) More remarkable effect in patients with a history ofstroke?
Figure. 3 shows the result of a subgroup analysis on the
proportions of patients with a favorable outcome (mRS
0-1) at 3 months after the initiation of the trial by presenceor absence of a history of stroke. When only the patients
without a history of stroke were analyzed, the proportions
were 52% in the rt-PA group and 47% in the placebo group,and the OR was 1.19 (95% CI: 0.89-1.59) with no significant
difference. However, in the analysis of the patients witha history, the proportions were 63 % in the rt-PA groupand 33 % in the placebo group, and OR was 3.33 (95 % CI:
1.35-8.22), indicating an unusually favorable outcome in
the rt-PA group [8]. What conditions led to such an unusual
phenomenon? (See Figure. 3 and think about it. Figure.4 andits footnote explain the idea of the editorial team.)
Given that the background variables are markedly biased(Figure. 2), and the significant difference, which cannot
be simply explained as a coincidence, was found in the
proportions of a favorable outcome (Figure. 3), it must be
concluded that the patients were allocated deliberately to
produce a positive result for rt-PA.
A comparison of outcomes adjusted by NIHSS scores has
been reported, but that for per protocol population (PPP)
adjusted by NIHSS scores has not. Unless the analysis wereconducted adjusting the severity of prior stroke in thepatients with a history, the result of ECASS-III cannot be
reliable.
Similarly, as a result of a subgroup analysis, in patients aged
65-year and older, the OR of the proportions of patientswith a favorable outcome (mRS 0-1) was 1.15 (95% CI: 0.801.64) and showed no significant difference. The total numberof deaths (mRS 6) and severest cases (mRS 5) was greater

Figure. 2: Bias in baseline characteristics in ECASS-III
Figure 3: The proportion of cases with a favorable outcome
by history of stroke

Odds ratio for patients with a history of stroke is 0.50 (p=0.003).
Difference in the average NIHSS score is not marked, but the odds ratio for theseverest cases is marked with significant difference: OR=0.48 (p=0.007).

Page 42 ・ MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3

cases with a favorable outcome: 0-1 on the mRS

in the rt-PA group (14.8 % vs 13.4 % ) in the initial analysis[5] although it was not significantly different. This result
is consistent with the finding that intracranial hemorrhage
occurred 6 times more frequently in patients treated with rtPA group.
ECASS-III involved patients aged 80-year and younger, andtheir NIHSS scores at baseline were low (average 10). It
included milder cases than those in other trials. Nevertheless,even with such a condition, the proportion of patients with ahistory of stroke, one of the background variables, was lower
in the rt-PA group, creating a more favorable condition for rtPA. When patients with no history of stroke are analyzed, no
significant difference is detected. Additionally, no significant
difference was found in patients aged 65-year and older, themain age group of actual patients, with poor safety result.
Based on these findings, we believe that the result of ECASSIII cannot provide evidence for approving a time window of
3 to 4.5 hours.
The 2010 meta-analysis and its problems
As mentioned in the guidelines (second edition) [6], theefficacy of rt-PA was not confirmed in ECASS, ECASS-II and
ATLANTIS-A for the use within 6 hours of onset, ATLANTIS-B
for the use within 3 to 5 hours of onset, and EPITHET for
the use within 3 to 6 hours of onset. However, in 2010, themeta-analysis of the 5 RCTs above as well as NINDS andECASS-III demonstrated that the proportion of patients withthe primary endpoint was significantly higher in the rt-PA
group when rt-PA was administered within 3 to 4.5 hours of
onset [11]. Indeed, it was higher in the rt-PA group (OR=1.34;
95% CI: 1.06-1.68). However, hemorrhage occurred certainly
more frequently (OR=3.61; 95% CI: 1.76-7.38), and mortality
was also slightly higher in the rt-PA group although it was
not significantly different (11.0% vs 10.1% , OR=1.22; 95% CI:
0.87-1.71).

Figure. 4: The proportion of cases with mRS (0-1) by history of stroke

It can be inferred that patients with a history of stoke would have a lessfavorable outcome than those without a history. This natural outcome is shownin the placebo group. However, in the rt-PA group, patients with a history ofstroke rather had a better outcome, and the OR was 1.57 (approximately 60%
increase) although it was not significant. Such a phenomena would not easily
occur unless the patients with a history of stroke in the rt-PA group included
those with very mild stroke such as lacunar infarction.

Various problems, such as bias in background variables
explained above, are found in the NINDS and ECASS-III
studies. Taking these into account, it is difficult to conclude
even with this combined analysis that rt-PA is more effective
than placebo when administered within 3 to 4.5 hours of
onset.
The 2014 meta-analysis using IPD and its problems
In 2014, another meta-analysis was conducted by adding
IST-3 study [9] to the 2010 analysis, using individual patients
data (IPD) of 6756 patients [12]. The IST-3 study was anopen trial that involved patients treated within 6 hours of
onset, and patients aged 81-year and older accounted for ahalf of the enrolled patients. The primary endpoints included
the proportion of patients with mRS (0-1) at 3 to 6 months,
symptomatic intracranial hemorrhage, and fatal hemorrhage
within 7 days, and 90-day mortality.
The analysis concluded “Irrespective of age or stroke
severity, and despite an increased risk of fatal intracranial
haemorrhage during the first few days after treatment,
alteplase significantly improves the overall odds of a good
stroke outcome when delivered within 4•5 h of stroke
onset.” The conclusion indicated that rt-PA is effective
even if patients are older and their conditions are severer
at baseline, and suggested to extend the coverage of theindications from that in the 2010 analysis.
However, the 2014 combined analysis covered the same
trials as the 2010 analysis except for IST-3, thus it inherited
similar problems. The 2014 analysis reported that when theentire individual patient data were analyzed, no significant
difference in background variables was found between thetwo groups. However, it can be suspected that the difference
in background variables detected in NINDS and ECASSIII became less apparent in other trials which could notprove the efficacy of rt-PA. Additionally, the 2014 analysis
included an open trial (IST-3), thus the conclusion above isinappropriate.
Among the patients treated within 3 to 4.5 hours of onset,
in particular, 70% of them was also involved in ECASS-III [5]and IST-3 [9]. As discussed earlier, there are problems in the
background variables, such as severity or presence of priorischemic stroke, in ECASS-III. Moreover, in IST-3, in patientstreated within 3 to 4.5 hours of onset, the proportion ofpatients with the primary endpoint is lower in the rt-PA
group than in the placebo (OR=0.73: 95 % CI: 0.50-1.07).
Mortality was higher in the rt-PA group at 7 days, 6 and 18
months when the treatment was given later than 3 hours
after onset [13]. In all cases, mortality was also higher in thert-PA group at 7 days (11% vs 7% , p=0.001), and mortalityof the two groups became similar at 6 months.
Efficacy is expected when rt-PA is given only within 1.5 hoursof onset
The analysis [3]by onset-to-treatment time, which was
published 5 years after NINDS [2], indicates that in patientstreated with rt-PA within 1.5 hours of onset, almost no bias
was found in background variables (Figure. 1). It suggeststhat many patients had a favorable outcome at 3 months,
thus rt-PA may have been effective. The apparent efficacy
observed in patients treated between 90 and 180 minutes
after onset is highly likely to have been caused by substantial
MED CHECK - TIP DECEMBER 2015 / Vol.1 No.3 ・ Page 43

Review
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Fig.ure 5: Distribution of Time from Onset to Start of Treatment among randomized patients

Most of the patients clustered close to the 90-minute limit. It raises suspicion that in prior to the initiationof the trial, rt-PA was predicted to be effective only in patients treated within 1.5 hours of onset. (Thehistogram was taken from the reference [3]. The comments are added by the editorial team.)bias. In spite of the bias, efficacy of rt-PA administered later
than 2.5 hours after onset was not demonstrated.
Moreover, in NINDS, most cases are concentrated in
the 80-90 minutes stratum (Figure. 5). This raises strong
suspicion that it was predicted at first place, before theinitiation of the trial, that rt-PA would be effective only when
delivered within 1.5 hours of onset.
In Practice
No clear evidence is available to show that rt-PA use
between 1.5 and 3 hours or 3 and 4.5 hours after onset ofischemic stroke would improve an outcome. When rt-PA
is given within 1.5 hours of onset, evidence suggests theefficacy although it is not robust. In practice, the use of rt-PA
should be restricted to patients treated within 1.5 hours ofsymptom onset.
In patients treated later than 1.5 hours up to 4.5 hours, theuse of rt-PA should be avoided until the bias in backgroundvariables in the previous clinical trials is rigorously adjusted
and the result of the adjustment is published.

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References
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outcome: the NINDS rt- PA stroke study. Neurology. 2000;55(11): 164955.
4) Hama R、t-PA (Alteplase) for the treatment of acute phase of ischemic
stroke. The Informed Prescriber. 2007：22(4)：44-46.
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6) The second edition of Guidelines for the rational use of rt-PA (Alteplase) by
the committee of the Japanese Society of stroke (revised Oct. 2012) http://
www.jsts.gr.jp/img/rt-PA02.pdf7) Clark WM1, Albers GW et al. The rtPA (alteplase) 0- to 6-hour acute stroke
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10) Alper BS, Malone-Moses M et al. Thrombolysis in acute ischaemic stroke:time for a rethink? BMJ 2015;350:h1075 d
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M
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The Informed Prescriber
2015

Vol.1

No.3

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD); TANIDA, Noritoshi (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); OHTSU,
Fumiko.(Pharmacist) ; TAKANO, Yoshihiko(MD[ pediatrician ]/Pharmacist) ; YANAGI, Motokazu (MD); YASUDA, Yoshinobu(Pharmacist)
Translators: NAKAMURA, Akari ; TAKAMACHI, Koji

Advisors:HONZAWA,Tatsuo (MD[GP]); IWAMOTO,Kayoko(Pharmacist);KIM,Mieko(Pharmacist); MUKAI, Junji (Pharmacist); SEGAWA,Yusuke;
SUMIDA, Sachie(MD [Dermatologist]); TERAOKA, Akio (Pharmacist) ;TOI, Chihiro (Pharmacist); UMEDA, Tadahito (MD[psychiatrist])
Editorial Officers: PRAXTONE, Mutsumi; SAKAGUCHI, Keiko
Production Team: MATSUMOTO, Koji ;UMEKI, Yukiko; SAKAGUCHI,
Keiko
Information Technology (IT):KURODA, Akira (Systems Engineer)
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