Brief Report

Dual Antiplatelet Therapy Improves Functional Outcome in

Patients With Progressive Lacunar Strokes
Anne Berberich, MD; Christine Schneider, MD; Tilman Reiff, MD;
Christoph Gumbinger, MD; Peter Arthur Ringleb, MD

Background and Purpose—In 20% to 30% of patients with lacunar strokes, early neurological deterioration (END) occurs
within the first days after stroke onset. However, effective treatment strategies are still missing for these patients. The
purpose of this study was to analyze efficacy of dual antiplatelet therapy (DAPT) in patients presenting with END.
Methods—Four hundred fifty-eight patients with lacunar strokes and corresponding neuroimaging evidence of lacunar
ischemia were retrospectively screened for END, which was defined by deterioration of ≥3 total National Institutes
of Health Stroke Scale points, ≥2 National Institutes of Health Stroke Scale points for limb paresis, or documented
clinical deterioration within 5 days after admission. Patients with END were treated with DAPT according to in-house
standards. Primary efficacy end point was fulfilled if National Institutes of Health Stroke Scale score at discharge
improved at least to the score at admission. Secondary end points were Rankin Scale score, further clinical fluctuation,
and symptomatic bleeding complications.
Results—END occurred in 130 (28%) of 458 patients with lacunar strokes. Ninety-seven (75%) of these patients were
treated with DAPT after END, mostly for 5 days. DAPT was associated with improved functional outcome. The primary
end point was met in 68% (66) of patients with DAPT compared with 36% (12) of patients with standard treatment
(P=0.0019). Further clinical fluctuations were absent in 79% (77) of patients with DAPT versus 33% (11) of patients
without DAPT (P<0.001). Symptomatic bleeding complications were not observed in any patient.
Conclusions—The results demonstrated potential positive effects of DAPT in patients with progressive lacunar
strokes.   (Stroke. 2019;50:00-00. DOI: 10.1161/STROKEAHA.118.023789.)
Key Words: lacunar stroke ◼ paresis ◼ stroke
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L acunar strokes represent about 25% of ischemic strokes

and are mostly associated with favorable outcomes.1,2
However, in 20% to 30% of patients with lacunar strokes,
presenting with END as off-label therapy. The aim of this ret-
rospective cohort study was to evaluate the efficacy of DAPT
in patients with progressive lacunar strokes.
early neurological deterioration (END) occurs within the first
days after stroke onset,2 and effective treatments are still miss- Methods
ing for these patients. The article adheres to the American Heart Association journals’ im-
The POINT trial (Platelet-Oriented Inhibition in New TIA plementation of TOP guidelines. Because of the data protection law,
and Minor Ischemic Stroke Trial) investigated the efficacy of detailed data supporting the findings of this study are only available
from the corresponding author upon reasonable request.
combination of aspirin and clopidogrel for 90 days regarding
We performed a retrospective observational cohort study in
reduction of stroke recurrence in patients with minor stroke patients with lacunar strokes based on a single stroke center hos-
and high-risk transient ischemic attack, defined by National pital database, analyzing data from January 1, 2010, to December
Institutes of Health Stroke Scale (NIHSS) score of ≤3 or 31, 2017.
ABCD2 score (age, blood pressure, clinical features, duration Detection of neuroimaging evidence of lacunar infarction was
mandatory for inclusion in this study. This evidence comprised a
of TIA, and presence of diabetes) of ≥4, and demonstrated a subcortical region of hypointensity on computed tomographic (CT)
reduced risk for major ischemic events but an increased risk scans or hyperintensity on diffusion-weighted sequences on magnetic
for major hemorrhage with combined treatment.3 However, resonance imaging (MRI), with largest diameter of ischemic lesion
this trial did not distinguish between stroke recurrence and ≤20 mm and corresponding with the clinical deficit. Patients also re-
stroke progression as cause for END nor did clarify the inclu- quired clinical deficits consistent with lacunar ischemia lasting for
≥24 hours. We excluded patients with imaging evidence of extracra-
sion of patients with lacunar strokes.4 nial or intracranial carotid stenosis, proximal vessel occlusion, clot
Our institutional guidelines allow the initiation of dual retrieval, evidence of cardioembolism, anticoagulant treatments, or
antiplatelet therapy (DAPT) in lacunar stroke patients with contraindications to DAPT. Evidence of cardioembolism was

Received August 3, 2018; final revision received December 23, 2018; accepted January 30, 2019.
From the Department of Neurology, Heidelberg University Hospital, Germany.
The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.118.023789.
Correspondence to Anne Berberich, MD, Department of Neurology, Heidelberg University Hospital, Im Neuenheimer Feld 400, D-69120 Heidelberg,
Germany. Email anne.berberich@med.uni-heidelberg.de
© 2019 American Heart Association, Inc.
Stroke is available at https://www.ahajournals.org/journal/str DOI: 10.1161/STROKEAHA.118.023789

1
 2  Stroke  April 2019

defined as detection of atrial fibrillation, intraventricular thrombus, or significant differences. As no adjustment for multiplicity was applied,
patent foramen ovale. All patients received in-hospital ECG monitor- P values should be interpreted descriptively.
ing for ≥24 hours and transthoracic echocardiography; patients ≤65 Ethical approval (S-109/2018) was obtained from the local ethics
years of age received transesophageal echocardiography. Arterial im- committee in Heidelberg; written informed consent was waived be-
aging with ultrasound, CT, or MRI was performed at the discretion cause of the retrospective analysis.
of treating physicians. Symptomatic bleeding complications were de-
fined as evidence of blood on CT or in susceptibility-weighted MRI
sequences at time point of clinical deterioration. As neuroimaging Results
was not routinely performed after the end of DAPT, only sympto- Four hundred fifty-eight patients with lacunar strokes were in-
matic bleeding complications were detected within this study. cluded in this study. Two hundred fifty-two patients received
Included patients were retrospectively screened for occurrence CT and MRI diagnostics as neuroimaging, 150 patients only
of END within 5 days after stroke onset, which was characterized
by worsening of existing clinical symptoms and particularly de-
received CT, and 56 patients received only MRI.
fined by deterioration of ≥3 total NIHSS points, deterioration of END occurred in 130 (28%) of the 458 patients with
≥2 NIHSS points for limb paresis, or description of fluctuating lacunar strokes. Eighty-five patients with END received
clinical symptoms in medical reports. Follow-up neuroimaging CT and MRI for neuroimaging, 26 patients received only
was performed after END to exclude new ischemic lesions and CT, and 85 patients received only MRI. First neuroimaging
cerebral hemorrhage.
Patients with END were divided into patients with initiation of was performed after a median of 4.26 hours (interquartile
DAPT (aspirin and clopidogrel) after END occurred and in patients range, 8.65) and MRI after a median of 19.6 hours (inter-
with single antiplatelet therapy only. DAPT was initiated as off-label quartile range, 31) after clinical onset. Sixty-six (14%) of
therapy and mostly continued for 5 to 7 days based on individual all patients and 32 (25%) of patients with END were treated
decisions and institutional standards according to which DAPT is with systemic thrombolysis at admission. END occurred in
allowed but not mandatory.
For analysis of efficacy of DAPT in patients with END, the 32 (48%) of the 66 patients treated with thrombolysis. The
NIHSS score at discharge was compared with the score at admis- frequency of single antiplatelet therapy before admission
sion as primary end point which was fulfilled if NIHSS score at was similar in patients with and without END (32% versus
discharge improved after END at least to the score at admission. 26%). END mainly consisted in deterioration of motor pa-
Secondary end points were fulfilled if (1) Rankin Scale score at
discharge was improved or stable after END compared with score
resis, ataxic paresis, or senso-motoric paresis (in 45, 25, and
at admission, (2) no further clinical fluctuation occurred, and (3) 55 patients, respectively). Clinical characteristics and out-
symptomatic hemorrhage was absent. comes of patients are presented in Table 1 and in Table I in
Patients’ characteristics and clinical outcomes were retrieved the online-only Data Supplement.
from electronic medical reports and NIHSS documentation. NIHSS DAPT was initiated after occurrence of END in 97 (75%)
score was performed at admission and at least every 6 hours mostly
of the 130 patients with progressive lacunar strokes. DAPT
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for ≥72 hours or until patients’ discharge in routine clinical work-up.

Statistical significance was assessed by fisher exact test using was mostly begun at the day of admission or 1 day after (33%
StatsDirect Version 3.1.14. P values of 0.05 were considered to show or 43%) and within 4 days in all patients and mainly continued

Table 1.  Clinical Characteristics of Patients With and Without END Subdivided in Patients With and Without Thrombolysis at Admission

Patients Without END (n=238) Patients With END (n=130)

With Thrombolysis Without Thrombolysis With Thrombolysis Without Thrombolysis
Clinical Characteristics (n=34) (n=294) (n=32) (n=98)
Age, median; (range) 74 (38–90) 69.7 (37–89) 69.3 (42–91) 70 (42–89)
Female gender, n 13 108 4 29
Hypertension, n 32 275 24 90
Diabetes mellitus, n 16 84 6 26
HbA1c, median (IQR) 6.1 (1.6) 5.7 (1.3) 5.7 (0.5) 5.8 (1)
Hypercholesterolemia, n 22 188 19 73
LDL-cholesterol, median (IQR) 112 (63) 120 (49) 124.5 (39) 127 (49)
Smoker, n 9 103 13 30
Prior TIA, n … 7 … …
Lacunar syndrome, n
  Motor paresis without sensory symptoms 9 70 12 33
  Ataxic paresis 3 64 2 23
  Senso-motor paresis 14 58 17 38
  Sensory symptoms without paresis 2 35 … 2
Hypertension, diabetes mellitus, or hypercholesterolemia was defined as diagnosis made before admission or systolic blood pressure ≥140
mm Hg, HbA1c ≥6.5, or LDL-cholesterol ≥120 mg/dL. For lacunar syndromes, only symptoms regarding paresis and sensory symptoms were
revised. Most patients had additional facial paresis or dysarthria. END indicates early neurological deterioration; HbA1c, hemoglobin A1c; IQR,
interquartile range; LDL, low-density lipoprotein; and TIA, transient ischemic attack.
 Berberich et al   Dual Antiplatelet Therapy in Lacunar Stroke   3

Table 2.  Efficacy of DAPT in All Patients With Progressive Lacunar Strokes and Subdivided in Patients With and Without Thrombolysis

All Patients (n=130) Patients With Thrombolysis (n=32) Patients Without Thrombolysis (n=98)
No DAPT No DAPT No DAPT
End Points DAPT (n=97) (n=33) P Value DAPT (n=17) (n=15) P Value DAPT (n=80) (n=18) P Value
Fulfilled primary end point 66 (68%) 12 (36%) 0.0019 14 (82%) 8 (53%) 0.13 52 (65%) 4 (22%) 0.0013
Fulfilled secondary end points
  Rankin Scale score 78 (80%) 24 (73%) 0.46 16 (94%) 9 (60%) 0.03 62 (78%) 15 (83%) 0.76
  No further fluctuation 77 (79%) 11 (33%) <0.001 15 (88%) 9 (60%) 0.1 62 (78%) 2 (11%) <0.001
  No bleeding complications 97 33 … 17 15 … 80 18 …
For efficacy end points, NIHSS and Rankin Scale score were compared between discharge and admission. P values of DAPT efficacy were calculated with
Fisher exact test. DAPT indicates dual anti-platelet therapy; and NIHSS, National Institutes of Health Stroke Scale.

for 5 days (87%). DAPT was significantly associated with an 7 days of DAPT, supporting the shorter treatment duration of
improved functional outcome: primary end point was met in 68% 5 days used in our clinical routine.
(66) of all patients treated with DAPT compared with 36% (12) Results of this study are limited by the retrospective na-
of patients without DAPT (P=0.0019; Table 2). Secondary end ture of analysis, small number of patients with DAPT after
point with absence of further clinical fluctuation was achieved thrombolysis, and the absence of randomization for differ-
in 79% (77) of patients with DAPT compared with 33% (11) ent treatments inducing potential selection bias. Reasons for
of patients without DAPT (P<0.001; Table 2). The end point of individual treatment decisions were retrospectively not de-
improvement of Rankin Scale score after END was not fulfilled terminable. Furthermore, efficacy end points consisting in
because no statistical significance was reached. Symptomatic comparison of NIHSS or Rankin Scale scores between dis-
bleeding complications were not observed in any patient treated charge and admission might underestimate DAPT efficacy but
with DAPT, regardless of prior thrombolysis or not. aimed to analyze clinically relevant, reliable, and sustained
In the subgroup of patients treated with systemic throm- DAPT efficacy. Therefore, a randomized clinical trial is neces-
bolysis at admission, END occurred in 32 (48%) of the 66 sary to validate DAPT efficacy in progressive lacunar strokes
patients and DAPT was initiated in 17 (53%) of these patients. which were not explicitly analyzed in the POINT trial.
Although DAPT did not reach statistical significance in ful-
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filling the primary end point or secondary end point of re- Conclusions
ducing further clinical fluctuations, the results indicated In conclusion, based on our study of 130 patients with END,
favorable effects of DAPT. Moreover, DAPT resulted in im- 5 days of DAPT within 4 days of onset of lacunar infarction
provement of Rankin Scale score in 94% (16) versus 60% (9) was associated with improved functional outcomes and no
of patients (P=0.03; Table 2). Systemic thrombolysis did not observed increased risk of symptomatic intracerebral bleed-
influence DAPT efficacy regarding efficacy end points once ing. The apparent overall benefit from DAPT in patients with
END occurred (Table II in the online-only Data Supplement). lacunar stroke and END needs testing in randomized trials.

Discussion Disclosures
We demonstrated a relevant improvement of functional out- None.
come after DAPT without increased risk for symptomatic
hemorrhage in progressive lacunar strokes which occurred References
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