Randomised comparison of subcutaneous heparin, intravenous heparin, and aspirin in unstable angina. Studio Epoorine sottocutanea nell'angina instabile (SESAIR) refrattorie group

1201

Randomised

_comparison

of subcutaneous

_heparin,

intravenous

heparin,

and

_aspirin

in unstable

_angina

Summary

Intravenous

_heparin

has been used in the control of

myocardial

ischaemia in

_patients

with unstable

_angina.

We

set out to assess the

_efficacy

of subcutaneous

_heparin

in

reducing myocardial

ischaemia in _patients with unstable

angina.

343 of 399

_patients

with unstable

angina

were

monitored for 24 h and 108 were

_refractory

to conventional

antianginal

treatment and were entered into a randomised multicentre trial. 37

_patients

were

_assigned

to

_heparin

infusion _(partial

_{thromboplastin}

time 1·5-2 times

baseline),

35 to subcutaneous

_{heparin (adjusted}

dose with

partial thromboplastin

time 1·5-2 times

_baseline),

and 36 to

_{aspirin (325}

_mg

_daily).

All had additional conventional

antianginal therapy.

After the run-in

_patients

were

monitored for 3

_days.

The

_{primary endpoint}

was reduced

myocardial ischaemia assessed

_by

the number of

_anginal

attacks, silent ischaemic

_episodes,

and duration of ischaemia per

day.

At 1 week and 1 month we accounted for

_anginal

attacks and other clinical events

_(myocardial

infarction, revascularisation procedures, and

_death).

Aspirin did not

_{significantly}

affect the incidence of

myocardial

ischaemia. On the first 3

_days,

infused and subcutaneous heparin

significantly

decreased the

frequency

of

_{angina (on}

_average

_by

91% and 86%,

respectively),

episodes of silent ischaemia

_(by

56% and

46%),

and the overall duration of ischaemia

_(66%

and

_61%)

versus run-in

_day

and

_{aspirin (p<0&middot;001 for}

all

_variables).

The favourable effects of _heparin

_therapy

remained evident

_during

follow-up.

Only

minor

_bleeding

_{complications} occurred. Subcutaneous

_heparin

is effective in the control of

_myocardial

ischaemia in patients with unstable

_angina.

Lancet 1995; 345: 1201-04

Clinica Medica and _Cardiologia, Center for the Heart and

Thrombosis _{Research, University} of Florence, Viale _{Morgagni 85,} 50134 Florence, Italy (Prof G G Neri Serneri MD, P A Modesti MD, L Poggesi MD, C Rostagno MD, C Tamburini MD, M Carnovali MD,

Prof G F Gensini MD); and Cardiology Department, University of

Bologna, Bologna (Prof A Branzi MD, G Melandri MD,

Prof B _{Magnani MD)}

Correspondence to: Prof Gian Gastone Neri Serneri

Introduction

Intravenous

_heparin

is a

_highly

effective treatment for the control of

_myocardial

ischaemia in

_patients

with unstable

angina.1,2

Continuous intravenous

_heparin

infusion is not

always

easily

feasible in small country

hospitals

or in

patients

treated at home because this treatment

_requires

pumps and careful

monitoring

of blood

clotting

by

partial

thromboplastin

time

(PTT).

Subcutaneous administration of

_heparin

is _easy, does not

_require

_pumps,

and,

if

_{appropriately}

_done,

_gives

the same

anticoagulant

effect

_(PTT

values within effective

_range)

as

_heparin

infusion.3 In the treatment of venous thromboembolism subcutaneous

_heparin

can be as effective as

_heparin

infusion and has a lower

frequency

of

bleeding.3,4

Subcutaneous

_heparin

_given

at low doses

_prevented

the recurrence of

_angina

in

_patients

_discharged

from

_hospitals

and can be used for medium-term and

long-term

treatment. 6,7 We set out to assess the effectiveness of subcutaneous

_{heparin, heparin}

_infusion,

and

_aspirin

on

myocardial

ischaemia in

_patients

with

_refractory

unstable

angina.

Patients and methods

Patients

Patients were admitted if _they had unstable _{angina-typical} chest

pain occurring at rest or on minimum effort with reversible ST

segment elevation or _depression of at least 0-1 mV 80 ms after

the J point, or a _{single episode} of chest pain lasting 20 min or

longer with serum concentration of creatine kinase less than

twice the upper limit of normal. All patients had had a painful

episode within 24 h of admission. Table 1 shows exclusion criteria. All patients were treated _orally with buffered aspirin 325 mg per day, isosorbide dinitrate 40 mg per day or more,

nifedipine 40 mg per day or _{more, and,} if not _{contraindicated,} metoprolol 200 mg per day. Other _{platelet-active drugs,}

non-steroid _{anti-inflammatory drugs,} oral _{anticoagulants, digoxin,} and _{antidepressant drugs} were excluded. Other medications,

such as diuretics or _{antihypertensives,} were _given if needed. We

1202

Table 2: _Demographic, clinical and angiographic

characteristics of the _study groups

continued _{prerandomisation} treatments _throughout. If chest _pain

persisted

or _recurred, nitrates were _{given sublingually} or

nitroglycerin

was infused _{intravenously.} After 1 day on

anti-anginal treatment, patients entered the 24 h run-in _{period during} which Holter

_monitoring

was done.

399 _{eligible patients} were admitted with unstable

_angina:

56 did not start the run-in _{period (table 1)} and 343 _patients were

admitted after _giving their informed consent. At the end of the run-in _{period only} those _patients who had had at least three ischaemic _{episodes during} the Holter monitoring period or one

documented anginal attack were admitted to the trial and were

randomised. Thus 108 _{(26%) patients} were randomised (table 1). The _patients of all groups had similar features (table 2).

Study design,

end-point,

and treatment

The study was a _prospective, randomised, multicentre trial. After

the 1 _day run-in _{period, patients} were randomised into three

treatment _groups. We continued trial

_therapy

for 3 _days and _continuously monitored electrocardiographic (ECG) measurements. _Follow-up was for 1 month. After this _3-day treatment, the dose of study treatment was left to the discretion of the medical staff who could either discontinue or modify the

dose but could not _change the _{antianginal therapy.} Data were

collected at the end of the 3 _{monitoring days} and thereafter 1 week and 1 month after randomisation.

The _{primary end-point} was reduced _myocardial ischaemia as seen _by the number of anginal attacks, the total number of ischaemic _{episodes (anginal} attacks _plus silent ischaemic

episodes), and overall duration of ischaemia (minutes per day)

during the 3 _days of Holter _monitoring. Patients were followed

up for a month after _{randomisation,} and the recurrence of _angina

(defined as recurrent chest _pain at rest with ischaemic ECG ST-T segment changes occurring despite maximal _antianginal

therapy), myocardial infarction, deaths, and coronary revascularisation _{procedures (percutaneous} transluminal

coronary angioplasty or _{coronary artery bypass grafting)} were

also recorded.

Patients were _randomly allocated to one of three treatment

groups: heparin infusion, subcutaneous heparin, or

aspirin.

Aspirin administration was withheld in the two _heparin treatment

groups but was recommended if _heparin was discontinued.

Heparin was infused _{intravenously,} with a _priming dose of

5000 IU followed _by 1000 _{IU per} h, and the dose was _adjusted

to maintain the PTT between 1-5 and 2 times the baseline. The PTT was assessed twice a _{day (at} 8 am and 6 _pm). In a

vs run-in _{day: *p<001, tp<0.OO5.} NS=not significnat.

Table 3: Ischaemic _episodes and overall duration of _myocardial ischaemia _during the _{monitoring period}

preliminary investigation we identified the most

_appropriate

subcutaneous _heparin dose according to _{body weight} and sex.

Subcutaneous _heparin

_{(Calciparina,}

_{Italfarmaco, Milan, Italy)}

was administered _{every 8} h. Male _{patients weighing} above 65 _kg received 10 000 IU; male _patients less than 65 _kg were _given

7500 IU. Female

_patients

received 7500 IU if

_{they weighed}

between 65 _kg and 90 kg, 10 000 IU if they

weighed

more than

90 _kg, or 5000 IU if _{they weighed} less than 65 _kg. In all _patients the first subcutaneous dose was given simultaneously with an

intravenous _priming dose of 5000 IU. The PTT was assessed before _{starting heparin} treatment and _{every day} 2 h before the afternoon _injection. If the PTT value was more than twice the

baseline, the next _heparin treatment was postponed for 3 h. If the

PTT value was less than 1-5 times the _baseline, the next _heparin

administration was _brought forward _by 2 h and further _injections were reset at 8 h intervals. The _algorithm of

_heparin

administration was _{regulated by} the _physicians of the clinical

centres. Buffered _aspirin was _{given orally} at _{325 mg per day.}

Assessments

Myocardial ischaemia was detected by Holter monitoring, which was done _during the run-in _period and the _following 3 _days of

treatment. _{Only progressive} ST segment shifts (0’1 1 mV) lasting at least 60 s were used as evidence of myocardial ischaemia.

Myocardial infarction was _diagnosed on the basis of typical chest

pain unrelieved _{by nitroglycerin} with new ST-T _changes or

Q-wavesB and new _doubling of creatine _{phosphokinase (CK)}

baseline levels with MB isoenzymes above 10%.

During the first 3 _days of treatment we recorded anginal

attacks, silent ischaemic _episodes, and overall duration of

ischaemia _{per day.} Each Holter _recording was _immediately read

blind of treatment _by

_physicians

of the clinical centre participating in the _study. All Holter _recordings were sent to the

coordinating centre for reviewing and final evaluation by three blinded observers.

On _days 4-7 the number of documented anginal attacks after

stopping continuous _monitoring was recorded. After the first

week the number of _anginal attacks was recorded weekly up to 1 month. _{Myocardial infarction, death,} and revascularisation

procedures were also recorded.

All _patients had _{coronary angiography.9,10 Bleeding}

complications were monitored _clinically and _by serial

measurement of _haemoglobin and haematocrit. Severe bleeding

was classified as intracranial haemorrhage or _haemorrhages

1203

Statistical

_analysis

From the data obtained _{previously by} our _group’ we _expected a

cumulative rate of three ischaemic _{episodes per day} and 30 min of ischaemia per day during the run-in period, with an overall

reduction of 15% for both variables in the aspirin group. To detect a 50% reduction in the event rate of _{heparin-treated} groups, each group needed at least 35 _{patients. End-point}

analysis was done _by an _independent biostatistical centre after enrolment was completed.

We _analysed events _according to intention to treat. A

secondary analysis was also done by censoring the events at the time when a _patient was withdrawn from trial _{therapy (efficacy}

analysis).

We used analysis of variance for _repeated measures with a

split-plot design for differences between days. For

_within-day

comparisons we used _{one-way analysis} of variance after we had assessed the homogeneity of variances with Levine’s test." I!

Multiple comparisons among treatment _groups were made with

Tukey’s

test. The _proportion of _patients in whom

_angina

recurred was _{compared by} Fisher’s exact _{and X2} tests. Results are

expressed as mean _{(SD). A p} value less than 0-05 was taken as

statistically significant. Results

Myocardial

ischaemia

108

_patients

were

_randomised,

37 to

_{heparin infusion,}

35

to subcutaneous

_heparin,

and 36 to

_{aspirin. During}

the run-in

_{period (day}

₁₎

the _groups were

_homogeneous

for the number of

_anginal

_attacks,

silent ischaemic

_episodes,

and for total duration of ischaemia

_{(table 3).}

Aspirin

did not

_{significantly}

affect the number of

anginal

attacks,

total ischaemic

_episodes,

or the duration of ischaemic

_episodes

_{(-28%, -8%,}

and

-6%,

not

significant

for all

_{variables) (table 3). By}

contrast,

heparin

infusion and subcutaneous

_heparin

induced a

significant

decrease in the number of

_anginal

attacks

_(-91%

and

- 86%),

silent ischaemic

_{episodes (-56%, -46%),}

and in the total duration of ischaemia

_(-66%,

-61%)

compared

with the run-in

_period

_(p<0-001).

Both treatments

differed in the three measures from the

_aspirin

group

(p<0-05,

p<0-001,

p<0-001

for both

_treatments)

(table 3).

In both

_heparin

treatment _groups

_myocardial

ischaemia was

easily

controlled because the number of

anginal

attacks and total ischaemic

_episodes

and the duration of ischaemia decreased

_already

_during

the first 24 h

(table 3).

Anginal

attacks and other events

_{during follow-up}

When we

_stopped

continuous Holter

monitoring,

24

patients

(65%)

remained on

_heparin

_infusion,

27

_(77%)

on subcutaneous

_heparin,

and 28

_(78%)

on

aspirin

for 4 extra

_{days. Analysis by}

intention to treat that limited

exposure to these 4

_days,

showed

_significant

_advantages

for

_heparin

treatments

_(heparin

infusion and subcutaneous

_heparin)

_compared

with

_aspirin:

22 of 36

patients

_{(61%) assigned}

to

_{aspirin experienced anginal}

attacks versus 6 of 37

_{(16%) given heparin}

infusion and 5 of 35

_{(14%) given}

subcutaneous

_heparin

_(XZ=23-792,

P<0-001).

Anginal episodes

occurred more

frequently

in

patients

who discontinued the

_heparin

treatments

₍₄

of 13

[30%]

for

_heparin

infusion and 2 of 8

_[25%]

for

subcutaneous

_heparin)

than in those who remained on

heparin

(2

of 24

_[8%]

for

_heparin

infusion and 3 of 27

[11%]

for subcutaneous

_heparin).

_However,

these

differences did not reach statistical

_{significance (X2=}

_1-691,

p=0-193

and

_X2=0-169,

_p=0-681,

_{respectively).}

Table 4: Clinical events _occurring within 1 month of randomisation

In the next 3

_weeks,

all

_patients

on

_heparin

infusion and 12 out of the 35 on subcutaneous

heparin

stopped

the treatment, whereas the other 23

_patients

of this group

were treated with 12-5 U

_daily.

_Angina

recurrence was more

frequent

in

patients

who

stopped

subcutaneous

heparin

(6

of

_12,

_50%)

than in those who remained on

heparin

treatment

₍₃

of

_23,

_13%)

_{(X2=3’870, p<0-49).}

Aspirin

treatment was continued in 25

_patients

and its discontinuation did not

_{modify angina frequency.}

In

_fact,

5 of 11

_patients

who discontinued

_aspirin

and 14 of 25

patients

who remained on

_aspirin

had

_{angina (X2=0’049,}

p=0825).

Angina

recurred more

frequently

in

_patients

on

aspirin

(14

of

_25,

_56%)

than in those on subcutaneous

heparin

(3

of

_23,

_13%)

_(X2=7.877,

_p<0-005).

At 1 month

follow-up

the distribution of events did not differ among

the three _groups

_{(table 4).}

Side-effects

Minor

_bleeding

events

_(epistaxis

or small

ecchymoses)

were seen in 2

patients

treated with

_aspirin

and in 2

patients

treated with intravenous

_heparin.

Discussion

These results show that subcutaneous

_heparin

is effective in the control of

_myocardial

ischaemia.

_Heparin

treatments

_by

intravenous infusion and subcutaneous administration decreased the number of

_anginal

attacks and silent ischaemic

_episodes

and reduced the overall

daily

duration of ischaemia in

_patients

with

_refractory

unstable

_angina.

The

_efficacy

of the two

_heparin

treatments was

supported

by

the

large

number of events,

even if the number of randomised

patients

was limited. The favourable effect of

_heparin

treatment was _prompt because it

_{significantly}

reduced the

_anginal

attacks and the duration of ischaemia after the first 24 h. Since all

patients

received

_{aspirin during}

the run-in

_period,

we cannot exclude a crossover effect of

_aspirin

in the

_efficacy

of

_heparin

treatments.

_However,

the effect of

_aspirin

was

unlikely

to have influenced the results because the

_efficacy

of

_{heparin progressively}

increased

during

the

_study

whereas

_aspirin

remained ineffective. From the intention-to-treat

_analysis

the benefit obtained from

_heparin

treatment

_during

the 3

_{monitoring days}

was still present at the end of the first week of observation. The differences

in recurrence of

angina

between

patients

who discontinued and

_patients

who remained on

heparin

treatment were not

_{statistically significant.}

_However,

our

results _agree with those of Theroux et al’2 who found a rebound of clinical _symptoms after

_heparin

discontinuation.

_Importantly,

our results suggest that

continuation of

_heparin

treatment for at least 4 weeks _may be useful in

_patients

with unstable

_angina:

_during

this

time subcutaneous

_{heparin prevented}

recurrence of

angina

whereas

_aspirin

did not.

Although

aspirin given during

the run-in

_day

to the

patients

of the three _{groups may} have contributed to the

1204

itself

_aspirin

could not affect

_myocardial

ischaemia in

unstable

_angina.

The ineffectiveness of

_aspirin

in the

control of

_myocardial

ischaemia as

opposed

to the

prevention

of vascular events _may have a dual cause: the

lack of effect on thrombin-induced

platelet aggregation

and the fact that thromboxane A2 is

_generally

_produced

by

monocytes within the vessel wall

itself,"

which

aspirin

is unable to reach in active form because of its

_rapid

hydrolysis by

esterases.’4

_Aspirin

_might

be

_expected

to halt the process of

platelet aggregation,

one of the factors

responsible

for

_myocardial

infarction

_complicating

unstable

_angina.15,16

_However,

_heparin

infusion

_prevented

myocardial

infarction more

_efficiently

than

_aspirin

_during

the acute

_phase

of unstable

_angina.2

_Likewise,

a combination of

_aspirin

_plus

_{anticoagulant}

seems to work better than

_aspirin

alone in

_reducing

the incidence of total ischaemic events in

_patients

with unstable

_{angina. ’7}

The results from these studies and from the present

investigation

thus confirm the

_prominent

role of increased thrombin formation in

_myocardial

ischaemia occurrence in

_patients

with unstable

_angina.’e3

Appropriate

doses of subcutaneous

_{heparin give}

a prompt, safe treatment that is as effective as

heparin

infusion for the control of

_myocardial

ischaemia in

patients

with unstable

_{angina refractory}

to conventional

antianginal

therapy.

Chairman and coordinator: GG Neri _{Serneri, University} of _Florence, Florence.

Investigators and institutions of the SESAIR study group: G F _Gensini, L Poggesi, P A Modesti, C Tamburini, C _Rostagno, Clinica Medica and

Cardiology, University of Florence, Florence; A Branzi, G _Melandri, F _Semprini, Dept of _Cardiology, University of Bologna, Bologna; A _Lotto, A Foresti, F _{Belluzzi, Dept} of _{Cardiology, Ospedale Maggiore IRCCS,}

Milano; G _Specchia, D _{Ardissino, Dept} of _Cardiology, Policlinico S

Matteo, Pavia; A _leri, M _{Margheri, Dept} of Cardiology, Ospedale S

Pietro, Fucecchio (Florence); M Sanguinetti, S Della _{Casa, Dept} of Cardiology, Ospedale di _{Lugo, Lugo (Ravenna);} A Maresta, E Varani,

Dept of _{Cardiology, Ospedale} degli Infermi, Faenza _(Ravenna); C _Parchi, S Negroni, Dept of Cardiology, Ospedale Nuovo, Imola _(Bologna); M Casaccia, A De Bernardi, Dept of _{Cardiology, Ospedale} Le Molinette, Torino; R Rigo, M P Benenati, Dept of Cardiology, Ospedale Civile,

Mirandola (Modena); G Caturelli, C Giglioli, Dept of Cardiology, Osepdali Civili Riuniti _SS, Giovanni e _{Paolo, Venezia;} P _Zonzin,

L _{Roncon, Dept} of _{Cardiology, Osp} di _{Rovigo, Rovigo;} D Bernardi,

F L _{Dini, Dept} of _{Cardiology, Ospedale} di _Barga, Barga (Lucca).

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