Cilostazol for Secondary Prevention of Stroke and Cognitive Decline

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Cilostazol for Secondary Prevention of Stroke and Cognitive Decline

Systematic Review and Meta-Analysis

Caroline McHutchison

,

Gordon W. Blair

,

Jason P. Appleton

,

Francesca M. Chappell

,

Fergus Doubal

,

Philip M. Bath

,

Joanna M. Wardlaw

Originally published10 Jul 2020https://doi.org/10.1161/STROKEAHA.120.029454Stroke. 2020;51:2374–2385

Abstract

Background and Purpose:

Cilostazol, a phosphodiesterase 3’ inhibitor, is used in Asia-Pacific countries for stroke prevention, but rarely used elsewhere. In addition to weak antiplatelet effects, it stabilizes endothelium, aids myelin repair and astrocyte-neuron energy transfer in laboratory models, effects that may be beneficial in preventing small vessel disease progression.

Methods:

A systematic review and meta-analysis of unconfounded randomized controlled trials of cilostazol to prevent stroke, cognitive decline, or radiological small vessel disease lesion progression. Two reviewers searched for papers (January 1, 2019 to July 16, 2019) and extracted data. We calculated Peto odds ratios (ORs) and 95% CIs for recurrent ischemic, hemorrhagic stroke, death, adverse symptoms, with sensitivity analyses. The review is registered (CRD42018084742).

Results:

We included 20 randomized controlled trials (n=10 505), 18 in ischemic stroke (total n=10 449) and 2 in cognitive impairment (n=56); most were performed in Asia-Pacific countries. Cilostazol decreased recurrent ischemic stroke (17 trials, n=10 225, OR=0.68 [95% CI, 0.57–0.81]; P<0.0001), hemorrhagic stroke (16 trials, n=9736, OR=0.43 [95% CI, 0.29–0.64]; P=0.0001), deaths (OR=0.64 [95% CI, 0.49–0.83], P<0.0009), systemic bleeding (n=8387, OR=0.73 [95% CI, 0.54–0.99]; P=0.04), but increased headache and palpitations, compared with placebo, aspirin, or clopidogrel. Cilostazol reduced recurrent ischemic stroke more when given long (>6 months) versus short term without increasing hemorrhage, and in trials with larger proportions (>40%) of lacunar stroke. Data were insufficient to assess effects on cognition, imaging, functional outcomes, or tolerance.

Conclusions:

Cilostazol appears effective for long-term secondary stroke prevention without increasing hemorrhage risk. However, most trials related to Asia-Pacific patients and more trials in Western countries should assess its effects on cognitive decline, functional outcome, and tolerance, particularly in lacunar stroke and other presentations of small vessel disease.

Introduction

Cerebral small vessel disease (SVD) causes 25% of ischemic stroke, most intracerebral hemorrhages, most vascular cognitive impairment and up to 45% of dementias, and other important aging-related comorbidities.¹ There is no specific treatment to prevent SVD progression. In a review of SVDs mechanisms and therapeutic agents with relevant modes of action,² we identified several licenced drugs including cilostazol, a phosphodiesterase 3′ inhibitor. In addition to mild antiplatelet effects,³ cilostazol has several actions targeting processes involved in SVD pathophysiology: endothelial dysfunction, myelin repair, neuroprotection, and inflammation.²

Cilostazol is used for stroke prevention in Asia-Pacific countries, but in Western countries it is used mostly for symptomatic peripheral vascular disease. Previous systematic reviews suggested that cilostazol prevented recurrent stroke.^4,5 However, further trials have been published since the last review, no review has assessed cilostazol’s effects in relevant subgroups and few assessed adverse effects (bleeding, headaches, palpitations, etc) that could limit cilostazol tolerance.

We performed a systematic review and meta-analysis to determine the effect of cilostazol on stroke recurrence, cognitive decline, radiological progression of SVD, intracerebral hemorrhage, death and adverse symptoms in patients with stroke or cognitive presentations of SVD.

Methods

We published the systematic review protocol on PROSPERO (registration No. CRD42018084742) in March 2018 and performed the review according to PRISMA standards.⁶ The data that support the findings of this study are available from the corresponding author upon request.

We searched MEDLINE and EMBASE between 1990 and July 16, 2019 (Data Supplement) for original articles reporting prospective randomized controlled trials of cilostazol in patients with stroke, SVD, mild cognitive impairment, or dementia. We also searched clinical trial registries (www.isrctn.com; https://eudract.ema.europa.eu/; www.strokecenter.org/), conference proceedings, bibliographies of review papers, previous systematic reviews, and trial papers for relevant trials not identified in the search, and finally for secondary publications of included trials that might provide additional outcomes.

We included randomized, controlled, unconfounded, trials in patients with stroke, mild cognitive impairment or dementia, or radiological features of SVD, who were randomized to treatment with cilostazol. Control groups received placebo tablets, another antiplatelet, or received no cilostazol (open label). We excluded trials only published as conference abstracts, where translation into English was not possible, or where the full text was not available.

We included trials that reported any of the following: recurrent stroke (all, ischemic, hemorrhagic), incident dementia, incident mild cognitive impairment, change in cognitive test scores including domain specific scores, intracranial hemorrhage, other major/fatal bleeding, other systemic bleeding complications, death, myocardial infarction, dependency in activities of daily living, symptoms related to cilostazol use (such as nausea, headache, palpitations), change in white matter hyperintensities, progression/development of lacunes, microbleeds, perivascular spaces, brain atrophy (assessed by volume or validated score).

Two reviewers screened titles and abstracts of all identified articles (G.W. Blair, C. McHutchison), independently performed full text review of relevant papers, extracted data from included papers using standardized forms, and cross-checked their findings.

We extracted data on trial setting (hospital, community, etc), number of participants, sex, inclusion illness, diagnosis method including cognitive testing, proportion with lacunar stroke, randomization methods, time from onset of inclusion illness to randomization, blinding, treatment dose, duration, control allocation, concomitant antiplatelet or other agents, methods of outcome assessment, and proportion of patients with outcomes as listed above by intention to treat populations. We assessed study quality using the CONSORT (Consolidated Standards of Reporting Trials) criteria.⁷

Discrepancies between the 2 reviewers were resolved by discussion and a third reviewer (Dr Wardlaw) who cross-checked all data extraction.

Meta-Analysis

We entered data into RevMan5 (version 5.3) software package. For most analyses, we grouped trials according to (1) their time to randomization (randomizing in acute/subacute versus later after stroke); and (2) use of other prescribed antiplatelet drug (none, cilostazol plus aspirin or clopidogrel versus aspirin or clopidogrel, cilostazol versus aspirin or clopidogrel) and meta-analyzed each outcome. We meta-analyzed symptoms by type. For death from all causes, we assumed no deaths in studies that did not report deaths. We used Peto odds ratio (OR) and 95% CIs for the meta-analyses, a preferred method where outcome events are infrequent.⁸

In exploratory sensitivity analyses, we ranked trials according to the proportion of patients with small vessel (lacunar) ischemic stroke, dichotomized into <40% and ≥40%, or unspecified. We also tested time from stroke to start of treatment and other antiplatelet drugs used.

We performed a meta-regression to test whether time to start treatment, proportion of patients with lacunar stroke, study duration, or comparison antiplatelet agent influenced the effect of cilostazol, using R version 3.6.2 (https://cran.r-project.org/) meta package.

We assessed risk of bias using funnel plots and heterogeneity using I² and χ² tests.

Results

We identified 572 articles but excluded 505 after abstract screening, and a further 43 after full text review (Figure 1). We included 20 unconfounded, original randomized controlled trials, published in 24 papers, including 10 505 participants (Table 1).

Table 1. Characteristics of Included Studies

Study and Country Where Done	Study Details					Cilostazol Group			Control Group
	Total n	Time From Diagnosis to Randomization	Treatment Duration	Patient Group	Stroke Subtype	Cilos-tazol n	Cilostazol Dose	Additional Treatment	Control n	Control Treatment	Control Dose
ARCC28	244	At least 2 wk to ≥365 d	4 wks	Ischemic stroke	NS	125	100 mg bd	Aspirin 100 mg daily	119	Placebo and aspirin	Aspirin 100 mg daily
Korea
CAIST23	458	48 h	90 d	Ischemic stroke	58% SVD, 28% LA, 1% CE, 12% other	231	200 mg daily	…	227	Aspirin	300 mg daily
Korea
CASID9	36	NS	24 wk	Probable Alzheimer Disease with white matter lesions	Not applicable	18	100 mg bd (2 wk) then 200 mg bd	…	18	Placebo	NS
Korea
CASISP26	719	1–6 mo	Up to 540 d	Ischemic stroke	NS	360	NS	…	359	Aspirin	NS
China
CATHARSIS13	163	2 wks to 6 mo	2 y	Ischemic stroke, >50% stenosis ipsilat intracran ICA or MCA	All non-CE ischemic stroke	83	200 mg daily	Aspiring 100 mg daily	80	Aspirin	100 mg daily
Japan
CSPS25	1067	1–6 mo	Cil=632.2±467.7 d	Ischemic stroke	75% lacunar, 14% atherothrombotic 9% mixed, 2% UK	533	100 mg twice daily	…	534	Placebo	100 mg twice daily
Japan			Cont=695.1±456.3 d
CSPS216	2672	Up to 26 wks	1–5 y	Non-CE ischemic stroke	65% lacunar, 32% atherothrombotic, 3% UK	1337	100 mg twice daily	…	1335	Aspirin	81 mg daily
Japan
CSPS.com17	1879	8–180 d	6 mo to 3.5 y	Non-CE ischemic stroke	49% lacunar, 42% atherothrombotic, 9% other/UK	932	100 mg twice daily	Aspirin 81 mg or 100 mg daily or Clopidogrel 50 mg or 75 mg daily	947	Aspirin or Clopidogrel	Aspirim=81 mg or 100 mg daily
Japan											Clopidogrel=50 mg or 75 mg daily
ECLIPse12	203	7 d	90 d	Lacunar ischemic stroke	100% lacunar	100	100 mg twice daily	Aspirin 100 mg daily	103	Placebo and aspirin	Placebo= 100 mg twice daily
Korea											Aspirin=100 mg daily
Guo et al27	68	1–6 mo	12 mo	Ischaemic stroke	NS	34	100 mg twice daily	…	34	Aspirin	100 mg daily
China
Johkura et al18	106	1–6 mo	6 mo	Non-CE ischemic stroke	NS but all supratentorial	57	200 mg daily	…	49	Aspirin	100 mg daily
Japan					c/o dizziness
LACI-111	57	Up to 4 y	Treatment (Cil: 9 wk; Cil+ISMN immediate start: 7 wk; Cil+ISMN delayed: 6 wk), Control: 11 wk	Lacunar stroke	100% lacunar	42	100 mg twice daily	Aspirin 75 mg or Clopidogrel 75 mg daily	15	Aspirin or clopidogrel	75 mg daily
UK
Lee et al24	80	Within 7 d	90 d	Ischemic stroke or TIA	NS	40	100 mg twice daily	Placebo Aspirin	40	Placebo and aspirin	Placebo=bd
Korea											Aspirin=100 mg daily
Nakamura et al19	76	48 h	6 mo	Non-CE ischemic stroke	47% SVD, 20% LA atheroma, 33% other/UK	38	100 mg twice daily	Aspirin 300 mg daily (4 d) then 100 mg daily	38	Aspirin	300 mg daily (4 d) then 100 mg daily
Japan
Ohnuki et al20	24	Within 1 wk	4 wk	Non-CE ischemic stroke	41% lacunar, 25% atherothrombotic, 6% other	13	200 mg daily	Aspirin 100 mg daily	11	Aspirin	100 mg daily
Japan
PICASSO22	1534	180 d	Median=1.9 y IQR=1.0–3.0	Ischemic stroke at high risk of ICH	Prior ICH or ≥2 microbleeds	766	100 mg bd	Aspirin placebo daily	768	Aspirin and placebo	Aspirin=100 mg daily
Korea											Placebo=bd
Sakurai et al10	20	>6 mo	6 mo	Possible Alzheimer Disease and SVD lesions	Not applicable	11	100 mg daily		9	Aspirin or Clopidogrel	Aspirin=100 mg daily
Japan											Clopidogrel=50–75 mg daily
Shimizu	507	24 h	3 mo	Non-CE progressing ischemic stroke	67% lacunar, 28% atherothrombotic, 5% other	251	200 mg daily	Aspirin 300 mg daily	256	Aspirin	Aspirin 300 mg daily
(Tohoku)21
Japan
TOSS14	135	2 wk	6 mo	Ischemic stroke, intracranial ICA or MCA stenosis	NS	67	100 mg bd	Aspirin 100 mg daily	68	Placebo and aspirin	Aspirin 100 mg daily
Korea
TOSS-215	457	2 wk	7 mo	Ischemic stroke, intracranial ICA or MCA stenosis	NS	232	100 mg bd	Aspirin 75–150 mg daily	225	Clopidogrel and aspirin	Clopidogrel=75 mg daily
Korea											Aspirin=75–150 mg daily

bd indicates twice daily; CAIST, Cilostazol in Acute Stroke Treatment; CASISP, Cilostazol Versus Aspirin for Secondary Ichemic Stroke Prevention; CATHARSIS, Cilostazol-Aspirin Therapy Against Recurrent Stroke With Intracranial Artery Stenosis; CE, cardioembolic; Cil, cilostazol; c/o, complaining of; cont, control; CSPS, Cilostazol Stroke Prevention Study; ICA, internal carotid artery; ICH, intracerebral hemorrhage; intracran, intracranial; ipsilat, ipsilateral; IQR, interquartile range; LA, large artery; MCA, middle cerebral artery; NS, not stated; PICASSO, Prevention of Cardiovascular Events in Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage; SVD, small vessel disease; TIA, transient ischemic attack; TOSS, Trial of Cilostazol in Symptomatic Intracranial Artery Stenosis; and UK, unknown.

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Figure 1. PRISMA flow chart of study identification.

Characteristics of Included Trials

The 20 trials had a median sample size of 183, range 20 to 2672. Eighteen trials included patients with stroke (n=10 449, Table 1) and 2 included patients with cognitive impairment or dementia of Alzheimer’s type and radiological evidence of SVD (n=56).^9,10

Of the 18 trials in patients with stroke, 2 only included patients with lacunar stroke (n=515),^11,12 3 only included patients with intracranial artery stenosis (n=755),^13–15 6 only included patients with noncardioembolic ischemic stroke (n=5264),^16–21 most trials excluded patients with cardioembolic stroke regardless of other inclusion criteria, and one trial included patients at high risk of intracerebral hemorrhage (n=1534).²² In 9/18 trials, the stroke was lacunar in ≥40% of participants (n=6943); in the other 9 trials, <40% of patients had a lacunar ischemic stroke or the subtype proportion was not specified (n=3262).

The time to randomization after diagnosis was <2 weeks in 8 (n=1940),^{12,14,15,19–21,23,24} between 2 weeks and 6 months in 5 (n=2123),^{13,18,25–27} and 6 months or later in 6 trials (n=6406; including the one trial in cognitive decline/dementia)^{10,11,16,17,22,28} and was not stated in the other trial in cognitive decline.⁹ The duration of trial treatment was 4 weeks in 3 (n=344),^19,20,28 10 weeks in 1 (n=57),¹¹ 4 months in 4 (n=1236),^12,20,22,23 6 to 8 months in 5 (n=753; including both trials in cognitive decline/dementia),^{9,10,14,15,18} 12 months in 1 (n=68),²⁷ and between 12 months and 5 years in 6 trials (n=8034).^{13,16,17,22,25,26}

Eight trials used placebo tablets, the rest were open label (Table 1). One trial in stroke and one in Alzheimer’s disease tested cilostazol versus control in the absence of any other antiplatelet drug; 9 trials tested cilostazol plus aspirin or clopidogrel versus aspirin or clopidogrel; 8 trials tested cilostazol versus aspirin or clopidogrel, and 1 trial tested cilostazol plus aspirin versus clopidogrel plus aspirin.

Of the 18 trials that included patients with stroke, one²⁸ did not record recurrent stroke outcomes, and one¹⁰ that included patients with cognitive impairment reported recurrent stroke; therefore, 18 trials provided data on recurrent stroke (all, ischemic, Table I in the Data Supplement). Sixteen trials reported recurrent hemorrhagic stroke, 18 reported death, 3 trials reported cognitive outcomes (2 trials in patients with cognitive impairment, one trial in stroke),^9–11 10 trials reported major cardiac outcomes, 7 assessed functional outcome (modified Rankin Scale) but only 5 gave results (precluding meta-analysis of effects of cilostazol on dependency), and about half the trials reported adverse symptoms (headache, nausea, palpitations, systemic bleeding; Table II in the Data Supplement). Outcomes are summarized in Table 2.

Table 2. Summary of Main Results

Outcome	Trials N	Participants Total N	Cilostazol n/N	Control n/N	OR/SMD (95% CI)	P Value	Subgroup I2 (%)	χ2P Value
All stroke	18	10 225	242/5127	384/5098	0.61 (0.52 to 0.72)	<0.00001	33.5	0.18
Ischemic stroke	18	10 225	210/5127	305/5098	0.68 (0.57 to 0.81)	<0.00001	44.5	0.11
Hemorrhagic stroke	16	9736	30/4885	72/4851	0.43 (0.29 to 0.64)	<0.0001	0	0.55
MACE	10	8948	320/4470	470/4478	0.66 (0.57 to 0.76)	<0.00001	2.5	0.39
Death, all cause	18	10 865	93/5123	144/5742	0.64 (0.49 to 0.83)	0.0009	18.0	0.30
Cognition	2	56	80	72	0.03 (−0.29 to 0.35)	0.84	0.0	0
Headache	14	9582	743/4804	413/4779	2.00 (1.76 to 2.28)	<0.00001	69	0.0001
Dizziness	9	6837	349/3419	292/3418	1.22 (1.04 to 1.44)	0.02	15	0.31
Palpitations	10	9147	281/4566	124/4581	3.14 (2.57 to 3.84)	<0.00001	54	0.02
Tachycardia	5	5396	145/2698	33/2698	3.74 (2.77 to 5.06)	<0.00001	43	0.15
Diarrhea	5	4064	303/2434	126/2403	2.21 (1.78 to 2.74)	<0.00001	41	0.13
Constipation	3	4664	189/2334	268/2330	0.68 (0.56 to 0.82)	0.0001	0	0.72
Nausea	4	3095	76/1548	53/1547	1.47 (1.02 to 2.11)	0.04	0	0.88
Systemic bleeding	12	8387	79/4211	102/4176	0.73 (0.54 to 0.99)	0.04	69	0.001
Sensitivity analysis: effect on ischemic stroke by subgroup
Ischemic stroke subtype*: <40% lacunar stroke	8	3262	68/1639	101/1623	0.72 (0.49 to 1.07)	0.10	14	0.32
≥40% lacunar stroke	9	6943	142/3477	222/3466	0.64 (0.52 to 0.79)	<0.0001	0	0.54
Test for subgroup difference χ2=0.27, P=0.60, I2=0
Time to treatment*: <2 wks of stroke (9.6 d)†	8	1940	21/972	19/968	1.1 (0.58 to 2.05)	0.78	0	0.81
≥2 wk of stroke (76 d)†	10	8285	189/4155	286/4130	0.65 (0.54 to 0.78)	<0.0001	0	0.52
Test for subgroup difference χ2=2.47, P=0.12, I2=59.5
Additional antiplatelet drugs: Cil vs no Cil, no antiplatelet	1	1067	30/533	57/534	0.51 (0.33 to 0.79)	0.003	n/a	n/a
Cil+Asp or Clop vs Asp or Clop	8	3044	40/1526	78/1518	0.51 (0.35 to 0.74)	0.0004	0	0.88
Cil vs Asp or Clop	9	6114	140/3068	170/3046	0.81 (0.65 to 1.02)	0.08	0	0.68
Test for subgroup difference χ2=.31, P=0.04, I2=68.3

Cil indicates cilostazol; MACE, major adverse cardiovascular events; n/a, not applicable; n/N, number of events/total number allocated to that group; OR, odds ratio; and SMD, standardized mean difference.

*Comparison is any cilostazol vs no cilostazol.

†Median time to randomization/treatment.

Recurrent Ischemic Stroke

Eighteen trials (n=10 225) reported recurrent ischemic stroke (cilostazol 5127, control 5098). Cilostazol decreased recurrent ischemic stroke (OR=0.68 [95% CI, 0.57–0.81]; P<0.0001), Figure 2, without heterogeneity. Most benefit appeared in the 9 trials testing cilostazol started >2 weeks after stroke (median 76 days; omitted in 3 trials) and given long term, where the ORs are all <1 regardless of comparator group or concomitant antiplatelet drug use (see sensitivity analyses below). In contrast, in the 8 trials starting cilostazol within 2 weeks of stroke (median 9.6 days; omitted in 4 trials) and assessing outcome at 1 to 4 months, the ORs all overlapped one, although the acute/subacute trials were smaller than the later-implementation/longer duration trials. A similar effect was seen for any recurrent stroke (18 trials, n=10 225, 5127 allocated cilostazol, 5098 allocated control) where cilostazol decreased the odds of any recurrent stroke (OR=0.61 [95% CI, 0.523–0.72]; P<0.00001), without heterogeneity (Figure I in the Data Supplement).

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Figure 2. Effect of cilostazol on ischemic stroke. CAIST indicates Cilostazol in Acute Stroke Treatment; CSPS, Cilostazol Stroke Prevention Study; and TOSS, Trial of Cilostazol in Symptomatic Intracranial Artery.

Hemorrhagic Stroke

Sixteen trials (n=9736) reported recurrent hemorrhagic stroke (cilostazol 4885, control 4851). Overall, cilostazol reduced hemorrhagic stroke (OR=0.43 [95% CI, 0.29–0.64]; P=0.0001), Figure 3, without heterogeneity. The pattern of effect was similar to that seen in all stroke and ischemic stroke although the reduced sample resulted in fewer individually significant results.

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Figure 3. Effect of cilostazol on hemorrhagic stroke. CASISP indicates Cilostazol Versus Aspirin for Secondary Ichemic Stroke Prevention; CATHARSIS, Cilostazol-Aspirin Therapy Against Recurrent Stroke With Intracranial Artery Stenosis; and CSPS, Cilostazol Stroke Prevention Study.

Major Adverse Cardiovascular Events

Ten trials reported a composite outcome of major adverse cardiovascular events (cilostazol 4470, control 4478). Cilostazol decreased major adverse cardiovascular events (OR=0.66 [95% CI, 0.57–0.76]; P<0.00001), without heterogeneity (Figure II in the Data Supplement). Most benefit occurred in trials testing long-term cilostazol starting 6 months or more after stroke, where summary ORs are <1 regardless of whether cilostazol was compared with placebo or aspirin or of concomitant antiplatelet drug use.

Death

Eighteen trials reported death from any cause (cilostazol 5123, control 5742). Overall, cilostazol decreased the odds of death (OR=0.64 [95% CI, 0.49–0.83]; P=0.0009), Figure III in the Data Supplement, without heterogeneity. Most benefit occurred in trials randomizing patients late after diagnosis while trials randomizing soon after stroke were more equivocal.

Cognition

Two trials provided meta-analyzable results (cilostazol 29, control 27; Figure IV in the Data Supplement), but data were too sparse to draw conclusions. One trial (LACI-1) that could not be meta-analyzed reported a mean difference (adjusted for baseline) in Trail Making Test A of −4.0 (−12.7 to 4.7; P=0.37).

Radiological Markers of SVD

Only 3 trials reported SVD imaging markers although each reported a different measure (silent infarcts, new ischemic lesion, microbleeds). Overall 55/557 participants allocated cilostazol developed an imaging lesion compared with 48/581 allocated control (OR=1.22 [95% CI, 0.81–1.84]; P=0.34).

Adverse Symptoms

The types of symptoms reported by each study varied (Table II in the Data Supplement). In general, patients allocated cilostazol had more headache, dizziness, palpitations, tachycardia and diarrhea, but less constipation and nonstroke bleeding events (Table 2; Figure V in the Data Supplement). There was no heterogeneity for the above outcomes apart from systemic bleeding and palpitations (palpitations I²=54%, χ²=19.43, P=0.02; systemic bleeding I²=69%, χ²=25.6, P=0.001).

Sensitivity Analyses

Lacunar Versus Nonlacunar Stroke

In the 8 trials with <40% or unstated proportion of patients with lacunar stroke (cilostazol 1639, control 1623), cilostazol did not reduce recurrent ischemic stroke (OR=0.72 [95% CI, 0.49–1.07]; P=0.10, without heterogeneity), Figure VIA in the Data Supplement. In the 9 trials with 40% or more patients with lacunar stroke (cilostazol 3477, control 3466; of which, 6 trials, total n=4964, included 58% or more lacunar strokes), cilostazol reduced recurrent ischemic stroke (OR=0.64 [95% CI, 0.52–0.79]; P<0.0001, without heterogeneity). However, the effect of cilostazol on recurrent ischemic stroke did not differ between the 2 subgroups (<40% or ≥40% with lacunar stroke), on formal testing (χ² for difference=0.27, P=0.60, I²=0%, P=0.60, without heterogeneity).

Time From Stroke to Treatment

Patients allocated treatment within 2 weeks of stroke, and where treatment was generally continued for no more than 4 months, those allocated cilostazol had similar rates of recurrent ischemic stroke (21/972) than those allocated control (19/968), OR=1.10 (95% CI, 0.58–2.05), P=0.78 without heterogeneity (Figure VIB in the Data Supplement). In patients starting treatment beyond 2 weeks after stroke (median), and where treatment was generally continued for 6 months to 5 years, those allocated to cilostazol had fewer recurrent ischemic strokes (189/4155) than those allocated control (286/4130), OR=0.65 (95% CI, 0.54–0.78), P<0.00001, without heterogeneity. However, there was no evidence of a between group difference (acute versus late, χ² 2.47, P=0.12, with moderate heterogeneity, I²=59.5%).

Concomitant Antiplatelet Drugs

Trials which randomized between cilostazol and no cilostazol in the absence or presence of concomitant aspirin or clopidogrel showed similar benefit for cilostazol (no aspirin, OR=0.51 [95% CI, 0.33–0.79]; P=0.003; all patients received aspirin or clopidogrel, OR=0.51 [95% CI, 0.35–0.74]; P=0.0004) (Figure VIC in the Data Supplement). However, in trials where cilostazol was compared with aspirin or clopidogrel, including one trial randomizing to cilostazol+aspirin versus clopidogrel+aspirin,¹⁵ there was no definite benefit of cilostazol (OR=0.81 [95% CI, 0.65–1.02]; P=0.08). Across the 3 subgroups, there was evidence of between-subgroup differences (χ², 6.31; P=0.04), and moderate heterogeneity (I²=68.3%). Restricting the analysis to trials comparing cilostazol with one antiplatelet drug in the absence of another antiplatelet drug by excluding the TOSS2 trial showed benefit of cilostazol over the other antiplatelet drug (OR=0.78 [95% CI, 0.62–0.99]; P=0.04, without heterogeneity) and removed the evidence of between-subgroup difference (χ2, 5.19; P=0.07), but retained heterogeneity (I²=61.4%).

Meta-Regression

Meta-regression of time to treatment, duration of treatment, and proportion of lacunar strokes, adjusted for comparator antiplatelet agent, did not identify any significant subgroup effects on outcomes of recurrent ischemic or hemorrhagic stroke.

Sources of Bias

The median trial quality was 23.5/37 (minimum 14, maximum 35), with methods sections attaining the lowest scores on average (Table III and Figure VII in the Data Supplement).

Funnel plots on all stroke and ischemic stroke showed some skew suggesting reporting bias but not for hemorrhagic stroke did not show any skew (Figure VIII in the Data Supplement).

Discussion

Cilostazol reduced recurrent stroke, recurrent ischemic stroke, recurrent hemorrhagic stroke, death and major adverse cardiovascular events compared with control, in the presence or absence of aspirin, or when compared directly with aspirin (data were limited for comparison with clopidogrel). Most benefit occurred in trials that randomized patients at 2 or more weeks after stroke and administered cilostazol for at least 6 months or longer, without evidence of increased risk with long-term treatment. There were very few data on the effect of cilostazol on functional outcome, cognitive decline, or radiological markers of SVD. Adverse symptoms such as headache, palpitations, dizziness, and diarrhea were clearly increased with cilostazol although, importantly, systemic bleeding events were reduced.

The review limitations are related to the available data and include variation between trials in antiplatelet drug use, times to randomization after stroke, durations of treatment, not reporting dependency outcomes, and lack of information on stroke subtypes. Included studies varied greatly in sample size and some studies had no events in either group for certain outcomes. Antiplatelet therapy has changed since some studies were completed. Guidelines now advice dual antiplatelets short term after transient ischemic attack or minor ischemic stroke, followed by clopidogrel longer term. Only one study compared cilostazol to clopidogrel and both groups also received aspirin.¹⁵ Only 2 trials recruited patients with cognitive presentations and only one trial in stroke assessed cognition. The median trial quality was moderate (23.5/37). Thus, despite the total available data from trials of cilostazol totaling over 10 000 patients, the conclusions have limitations. There were also strengths of the review, including prospective protocol registration, assessment of methodological quality, double assessment of papers and data extraction, and careful harmonization of the trials for analysis.

Cilostazol may have more benefit on several outcomes where participants were randomized later after stroke. Although arbitrary, the trials naturally dichotomized into those randomizing within 2 weeks of stroke and those randomizing at >2 weeks after stroke, of which about a third randomized between 2 weeks and 6 months and 2 thirds randomized after 6 months. Trials randomizing >6 months after stroke had long durations of treatment and follow-up. Thus, the apparent benefit of cilostazol in trials randomizing late rather than early may reflect the paucity of acute trials, shorter duration of treatment, higher proportion of lacunar strokes, or that cilostazol is less effective in preventing early recurrent stroke. Similar results have been seen with another phosphodiesterase inhibitor dipyridamole (PDE5 inhibitor) with mild-antiplatelet and proendothelial effects,² which reduced stroke recurrence while increasing headache, mostly in Western populations. The risk of stroke recurrence varies by stroke subtype, atherothromboembolic stroke recurrence risk being the highest immediately after transient ischemic attack/minor stroke, then declining, whereas lacunar stroke has lower risk of early recurrence but the rate remains elevated in the longer term.

Cilostazol’s apparent greater benefit late after stroke could reflect several possible mechanisms. Weaker antiplatelet effects³ and hence inferior stroke prevention compared with aspirin or clopidogrel early after transient ischemic attack/stroke (when stronger antiplatelet activity may be more beneficial) is supported by the neutral effect of cilostazol on ischemic stroke recurrence compared with aspirin or clopidogrel (Figure VIC in the Data Supplement). Increasing benefit of cilostazol late after stroke was also demonstrated in CASISP, which found no difference in recurrent stroke between cilostazol and aspirin within 6 months of stroke, but increasing benefit of cilostazol versus aspirin thereafter.²⁶ The increased benefit of cilostazol later after stroke may reflect that its mechanisms of action are more relevant to lacunar stroke where recurrence occurs late, supported by increased benefit in trials including more patients with lacunar stroke (Figure VIA in the Data Supplement). Potential benefits for lacunar stroke include endothelial stabilization, improved myelin repair, and better astrocyte-to-neuronal energy supply,^2,11 all of which may take some time to accrue. The lower cerebral and systemic hemorrhage risks would also confer benefit over other antiplatelet drugs, which typically have higher bleeding risk the longer they are given, a reason for early stopping of the SPS3 Trial (dual versus single antiplatelet drugs) for lacunar stroke²⁹ and seen in the present meta-analysis even in the presence of other antiplatelet drugs. The PICASSO (PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage) trial suggests that the benefits of cilostazol may extend to reducing recurrent stroke and systemic bleeding even in patients at high risk of intracerebral hemorrhage.²²

More data are needed to overcome the limitations of the current data, to determine the effect of cilostazol on functional and cognitive outcomes after stroke, and on delaying cognitive decline. If the effects of cilostazol seen in laboratory models translate to people (myelin repair, improved neuronal energy supply, and endothelial stabilization) and help to prevent progression of brain injury, then cilostazol might also prevent physical decline seen in SVD. Future studies should compare cilostazol to modern antiplatelet regimes, stratify patients by stroke or cognitive impairment, provide more data on cognitive, imaging and functional outcomes, and on tolerability and compliance. Several ongoing studies address these issues. LACI-2 (ISRCTN 14911850) is assessing cilostazol long-term after lacunar ischemic stroke in the UK including 1-year cognitive and brain magnetic resonance imaging follow-up (target n=400). The COMCID trial (Asia-Pacific) is assessing cilostazol’s effects on cognitive function, incident dementia, and hippocampal volumes (NCT02491268). Other trials are assessing short-term effects of cilostazol on cerebrovascular reactivity (eg, Oxford Hemodynamic Adaptation to Reduce Pulsatility Trial [OxHARP], NCT03855332, target n=76).

Cilostazol shows promise for ischemic stroke prevention, with lower risk of hemorrhagic complications, particularly long term. Its place in stroke therapy may be in chronic secondary prevention rather than the acute phase. However, most data are from Asia Pacific countries where stroke etiologies and other factors may differ from other world regions, hence the need for more data. Despite its encouraging safety profile (lower bleeding risk and death), cilostazol causes several symptoms (headache, palpitations, diarrhea, nausea), which may limit tolerance, requiring more data to guide future routine use. It is licenced in Europe and the Americas for treatment of symptomatic peripheral vascular disease and stroke prevention where other antiplatelet agents have failed or are not tolerated. However, more evidence is needed before it is used more widely in stroke in routine practice.

LIVE from SNIS(Society of NeuroInterventional Surgery’s): The stroke trials you need to know about

Notice how fucking appalling this is. NOTHING on stopping the neuronal cascade of death  or solving ANY of these 13 problems in stroke with nothing to address them.

WE HAVE NO STROKE STRATEGY AND NO STROKE LEADERSHIP.  Your children and grandchildren are screwed unless we get survivors in charge.

The latest here:

LIVE from SNIS(Society of NeuroInterventional Surgery’s): The stroke trials you need to know about

5 August 2020

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From acute interventions to endovascular therapy indication expansion, Sunil Sheth from McGovern Medical School at UTHealth, Houston, USA, kick-started the Society of NeuroInterventional Surgery’s (SNIS) annual meeting (4–7 August) by outlining an array of recently completed, and ongoing stroke trials.

“If I do not include your favourite trial, please forgive me,” he said. “Our goal today is to cover the full range of acute ischaemic stroke studies. From start to finish I will try to have representation from trials around the globe.”

He explained to the audience that he has organised the trials by the segment of care; trials pertaining to prevention of stroke, systems of care, acute interventions, endovascular therapy indication expansion, and stroke recovery trials.

Prevention

The first trial Sheth alluded to was ARCADIA (Artrial cardiopathy and antithrombotic drugs in prevention after crypotogenic stroke). In this study, patients with embolic stroke of uncertain source (ESUS) are randomised to aspirin or apixaban. Sheth said it aims to answer the question: Which of these approaches is better at reducing the risk of subsequent or first-time stroke? The key criteria are ESUS, and evidence of atrial cardiopathy.

Next, he said that CREST2 (Carotid revascularisation and medical management for asymptomatic carotid stenosis trial)—a follow-up of CREST1—is investigating whether carotid revascularisation is, in fact, beneficial in preventing stroke. “The patients in this trial get randomised to either medical therapy or stenting endarterectomy. They have to have ≥70% stenosis and it has to be treatable. Like ARCADIA, this trial is enrolling, also with a target completion date of 2022,” Sheth explained.

Stroke systems of care

Pointing to trials pertaining to systems of care, he discussed the RACECAT trial—a prehospital stroke trial. “In Barcelona, Marc Ribo’s group is trying to answer the question: Which is the better routing strategy in the prehospital environment? Is it going from EMS directly to a primary stroke centre, or from EMS—bypassing the primary stroke centre—and going directly to a comprehensive stroke centre?

“The patients are being pre-screened and have to have some suspicion of LVO with a Rapid Arterial Occlusion Evaluation (RACE) score >4, and the trial is being conducted in areas where the local hospital cannot perform thrombectomy. This is a trial that is very closed to being completed, and I am looking forward to those results.”

The TRIAGE (Treatment strategy in acute ischemic large vessel stroke: prioritise thrombolysis or endovascular treatment) trial is similar, he said. In Denmark, patients are being randomised in the prehospital setting—either going directly to a primary stroke centre for IV tissue plasminogen activator (tPA) and then to a comprehensive stroke centre, versus going directly to the latter.

The last trial regarding optimising stroke systems of care he discussed was the BEST-MSU (Benefits of stroke treatment delivered using a mobile stroke unit) trial. Here, patients were randomised to either getting mobile stroke unit care versus standard EMS care, and had to be eligible for IV tPA. “They enrolled their last patient last week, so they are now completing their follow up and we should be hearing from them soon.”

Acute Interventions: Drugs

The next set of trials are interventional trials that involve medical therapies, Sheth told the SNIS online audience.

“The first is MOST (Multi-arm optimisation of stroke thrombolysis); a trial randomising patients that get IV tPA to receive either argatroban, eptifibatide, or placebo,” he said, adding that patients receive the study drug within one hour of IV tPA, and thrombectomy is allowed in these patients.

In addition, the TIMELESS (Tenecteplase in stroke patients between 4.5 and 24 hours) trial is randomising patients to either a single bolus dose of tenecteplase or placebo. Sheth noted that these patients are not IV tPA eligible, randomised between 4.5 to 24 hours of stroke onset. However, they have to have an LVO, and their imaging criteria must include a mismatch on CT perfusion and MRI. Like the MOST trial, TIMELESS is currently enrolling.

Sheth next introduced the first of several MR CLEAN follow-up trials. “MR CLEAN MED, a medical trial with a 2×2 factorial trial, includes patients with thrombectomy that was planned (with an LVO), getting randomised either to receive 300mg aspirin, or not, and/or a heparin bolus dose drip, or not. This is an open label study, so these are patients that are getting thrombectomy, with the drugs infused at the time of groin puncture, or right after IV tPA is completed.” He added that the study started in 2018, and is a third of the way through enrolment.

In terms of the MR CLEAN NO IV trial, Sheth told viewers that this explores the question of whether or not IV tPA is useful when patients are also getting thrombectomy. Key criteria include that patients must be IV tPA eligible (within 4.5hours), and have to have an LVO. “One of the unique aspects of this trial, like the original MR CLEAN trial, is that delayed consent is allowed, so you can screen and enroll, and randomise patients without consent upfront. Because of this, they have been enrolling very well; faster than expected, so the trial should be completed very soon,” Sheth highlighted.

Another trial looking to answer the same question is the SWIFT DIRECT (Bridging thrombolysis versus direct mechanical thrombectomy in acute ischaemic stroke) trial, which is randomising patients to thrombectomy (with Solitaire; Medtronic) with or without IV tPA. Again, these are IV tPA eligible patients with LVO, and an Alberta Stroke Program Early CT score (APECTS) ≥4. The estimated completion of this trial is 2022.

Endovascular therapy indication expansion

Sheth displayed the first set of four trials to the SNIS viewers, describing them as the “so-called large core trials”, which are exploring whether thrombectomy is helpful in patients that are presenting with an established moderate to large stroke. TESLA (Thrombectomy for emergent salvage of large anterior circulation ischaemic stroke) is testing thrombectomy versus medical management for patients with large cores (which is defined here as an ASPECTS 2–5 in patients up to 24 hours of stroke onset. In this study, internal carotid artery (ICA) or M1 occlusions are allowed, but tandem occlusions are being avoided. Currently over 40/300 patients have been enrolled.

“Then we have the TENSION trial out of Europe, which again explores thrombectomy versus medical management for large core,” Sheth explains. However, while the study has similar inclusion criteria to TESLA, large core is defined as ASPECTS 3–5. Sheth said it has a larger sample size (n=655), with around 93 patients enrolled so far.

Regarding the remaining large core trials, Sheth said the LASTE (Large stroke therapy evaluation–ASPECTS 0–5) trial, part of the IN EXTREMIS cohort, defines large core as ASPECTS 0–5, up to 6.5 hours after stroke onset, and also includes ICA or M1 occlusions, while the SELECT 2 trial is similar, but a “major difference” is that CT perfusion is required in these patients.

“At the opposite end of the spectrum, we have the low National Institutes of Health Stroke Scale [NIHSS] studies,” Sheth said.

First, he introduced the ENDOLOW (Endovascular therapy for low NIHSS ischaemic strokes) trial, which examines thrombectomy (with Embotrap; Cerenovus) versus medical management (with possible thrombectomy rescue) in patients with ICA or M1 occlusions that have an NIHSS score 0–5. “Imaging criteria for this trial is ASPECTS ≥6,” Sheth added, “and there are also some CT perfusion and MRI criteria as well. The trial is currently enrolling, estimated to be completed by next year.”

According to Sheth, the MOSTE (Minor stroke therapy evaluation—NIHSS 0–5) trial is also looking into thrombectomy versus medical management, with possible thrombectomy rescue within 24 hours, with ASPECTS screening as an inclusion requirement.

“In terms of the EVT indication expansion trials, we also have a Chinese endovascular trial (BAOCHE), investigating whether or not basilar artery occlusion patients benefit from thrombectomy, which is still an outstanding question, at least from a clinical trial point of view,” he told the SNIS audience.

Lastly, he explained that the MR CLEAN LATE trial is a late time window trial. He proposed that it is different from DAWN and DEFUSE 3 as CT perfusion is not required. Instead, the imaging requirement is CTA collateral grading.

Acute interventions: Devices

Next, Sheth alluded to a number of studies looking at devices, which are mostly industry-sponsored. The EXCELLENT trial, sponsored by Cerenovus, is studying the Embotrap through a prospective registry. The COMPLETE study is looking at the Penumbra aspiration catheters and the 3D separator. Sheth said this trial is now complete, and the results should be out soon. PROST by Phenox is looking at their Preset device versus the Solitaire (Medtronic) device. “This is not a registry,” Sheth explained, “but a randomised trial between two treatment approaches.”

The TIGER trial that Rapid Medical has recently completed investigated their Tigertriever as a prospective study. According to Sheth, Imperative Care’s trial is coming soon, which seeks to compare their Zoom aspiration catheters to Solitaire or Trevo (Stryker). Finally, he said the INSIGHT study by Penumbra is a registry for thrombus collection in thrombectomy and intracerebral haemorrhage evacuation. “But this is not a device trial, per se,” he added.

Stroke recovery trials

“There is a whole suite of recovery trials, but I am going to focus on two,” Sheth told the audience. PISCES III (Investigation of neural stem cells in ischaemic stroke) involves testing a stereotactic injection of stem cells into a region adjacent to the infarct, versus sham surgery. Key criteria for this, according to Sheth, include some residual arm function, stroke within six to 24 months, and sufficient language function. Enrolment for PISCES III is complete.

The concluding trial of his talk referred to one examining transcranial direct current stimulation (tDCS) and task-specific practice for post-stroke neglect. The design involves comparing bilateral parietal tDCS versus bilateral primary motor cortex tDCS, versus sham plus task-specific practice. In terms of its status, Sheth said it is still enrolling.

For more stories from SNIS 2020, click here.

New molecule reverses Alzheimer's-like memory decline

Is your doctor and stroke hospital looking at this and IMMEDIATELY realizing this might be a solution to your 5 lost cognitive years from your stroke. 

Or is your doctor and stroke hospital doing nothing with this? Do you prefer your incompetence NOT KNOWING? OR NOT DOING?

Their reasons for doing nothing?

Laziness? Incompetence? Or just don't care? No leadership? No strategy? Not my job?

The latest here.

New molecule reverses Alzheimer's-like memory decline

MedicalXpress Breaking News-and-Events|August 5, 2020

A drug candidate developed by Salk researchers, and previously shown to slow aging in brain cells, successfully reversed memory loss in a mouse model of inherited Alzheimer's disease. The new research, published online in July 2020 in the journal Redox Biology, also revealed that the drug, CMS121, works by changing how brain cells metabolize fatty molecules known as lipids.

"This was a more rigorous test of how well this compound would work in a therapeutic setting than our previous studies on it," says Pamela Maher, a senior staff scientist in the lab of Salk Professor David Schubert and the senior author of the new paper. "Based on the success of this study, we're now beginning to pursue clinical trials."

Over the last few decades, Maher has studied how a chemical called fisetin, found in fruits and vegetables, can improve memory and even prevent Alzheimer's-like disease in mice. More recently, the team synthesized different variants of fisetin and found that one, called CMS121, was especially effective at, improving the animals' memory, and slowing the degeneration of brain cells.

In the new study, Maher and colleagues tested the effect of CMS121 on mice that develop the equivalent of Alzheimer's disease. Maher's team gave a subset of the mice daily doses of CMS121 beginning at 9 months old—the equivalent of middle age in people, and after the mice have already begun to show learning and memory problems. The timing of the lab's treatment is akin to how a patient who visits the doctor for cognitive problems might be treated, the researchers say.

After three months on CMS121, at 12 months old, the mice—both treated and untreated—were given a battery of memory and behavior tests. In both types of tests, mice with Alzheimer's-like disease that had received the drug performed equally well as healthy control animals, while untreated mice with the disease performed more poorly.

To better understand the impact of CMS121, the team compared the levels of different molecules within the brains of the three groups of mice. They discovered that when it came to levels of lipids—fatty molecules that play key roles in cells throughout the body—mice with the disease had several differences compared to both healthy mice and those treated with CMS121. In particular, the researchers pinpointed differences in something known as lipid peroxidation—the degradation of lipids that produces free radical molecules that can go on to cause cell damage. Mice with Alzheimer's-like disease had higher levels of lipid peroxidation than either healthy mice or those treated with CMS121.

"That not only confirmed that lipid peroxidation is altered in Alzheimer's, but that this drug is actually normalizing those changes," says Salk postdoctoral fellow Gamze Ates, first author of the new paper.

The researchers went on to show that CMS121 lowered levels of a lipid-producing molecule called fatty acid synthetase (FASN), which, in turn, lowered levels of lipid peroxidation. When the group analyzed levels of FASN in brain samples from human patients who had died of Alzheimer's, they found that the patients had higher amounts of the FASN protein than similarly aged controls who were cognitively healthy, which suggests FASN could be a drug target for treating Alzheimer's disease.

While the group is pursuing clinical trials, they hope other researchers will explore additional compounds that may treat Alzheimer's by targeting FASN and lipid peroxidation.

"There has been a big struggle in the field right now to find targets to go after," says Maher. "So, identifying a new target in an unbiased way like this is really exciting and opens lots of doors."

To read more, click here

Preemptive Blood Thinners Tied to More Deaths in Hospitalized COVID-19 Patients

So now YOU need to find out what the difference is between preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing.  I had several Lovenox shots when my INR was out of whack but have no clue if that was
therapeutic or prophylactic.  I'm still going to be requesting heparin or Lovenox shots because I don't want all the microthrombi circulating  in my blood causing all kinds of havoc. But don't listen to me, I'm not medically trained, you'll just have to hope your doctor guesses correctly because there is not enough information yet to create protocols. I suppose you'll just have to wait a couple of years before you get COVID-19 to allow the research to inform practice. 

The latest here:

Preemptive Blood Thinners Tied to More Deaths in Hospitalized COVID-19 Patients

Risk of in-hospital mortality 2.3 times greater versus prophylactic anticoagulation, but many questions remain

by Zeena Nackerdien PhD, CME Writer, MedPage Today 2020-08-05

Study Authors: Jishu K. Motta, Rahila O. Ogunnaike, et al.

Target Audience and Goal Statement: Infectious disease specialists, hematologists, pulmonologists, critical care specialists

The goal of this study was to compare clinical outcomes of patients with COVID-19 who received preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing.

Question Addressed:

• What was the impact of preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing on in-hospital mortality among COVID-19 patients?

Study Synopsis and Perspective:

Researchers have sought to examine the possible benefits of using anticoagulants to treat COVID-19 patients, with mixed results. In one study of patients with severe COVID-19, use of prophylactic low-molecular-weight heparin (LMWH) seemed to improve survival compared with no anticoagulation therapy.

Action Points

• Among patients hospitalized with COVID-19, risk of in-hospital mortality was 2.3 times greater in those receiving preemptive therapeutic-dose anticoagulation compared with standard prophylactic dosing, according to a study from two acute care U.S. hospitals.
• Note that study limitations included the retrospective study design, lack of randomization, no capture of mortality after the patients left the hospital, unmeasured confounding, and limited generalizability.

In another study, there was no significant change in in-hospital mortality in COVID-19 patients who received anticoagulants compared with those who did not, though a decreased length of hospital stay was noted. In addition, use of anticoagulation was associated with a significant decrease in mortality among mechanically ventilated patients.

In a retrospective study published on the medRxiv preprint server, Jishu Kaul Motta, MD, of Danbury Hospital in Connecticut, and colleagues hypothesized that preemptive treatment with therapeutic anticoagulation could lower the risk of a COVID-19-associated prothrombotic state leading to increased mortality.

However, they observed more deaths among those treated preemptively versus prophylactically with anticoagulants, and they also showed that patients with more severe disease (C-reactive protein ≥200 mg/L) did not experience clinical improvement in outcomes with preemptive therapeutic anticoagulation.

These findings highlight the need to consider the risks and benefits for the patient and the healthcare system when using preemptive therapeutic-dose anticoagulation in hospitalized patients with COVID-19.

Of 501 hospitalized SARS-CoV-2-positive adults across two acute care hospitals located in western Connecticut, 374 patients were included in the study in April 2020, with follow-up through June 12. The study excluded patients who received therapeutic-dose anticoagulation specifically for a thrombotic indication.

Demographic variables were collected via hospital billing inquiries, while clinical variables were taken from patients' medical records.

Patients had an average age of 64.7 years, and men made up more than half of the sample (58.6%). The majority were white (54%); African-Americans constituted 9.9% of the full sample. A third of the patients smoked, and heart disease was the most common comorbidity (56.7%), followed by diabetes (31.6%). The prophylactic and therapeutic anticoagulation groups consisted of 299 and 75 patients, respectively.

The risk of mortality was also determined among 104 patients with C-reactive protein levels ≥200 mg/L.

Most of the patients took enoxaparin(Lovenox) during their inpatient stay (93.5%), and 14.8% took heparin. The prophylactic dosage of enoxaparin was defined as 30 or 40 mg given subcutaneously every day, while the therapeutic dose was defined as 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously daily or based on renal function, or higher doses titrated to an anti-factor Xa range of 0.6 to 1 IU/mL (for twice daily dosing) and 1 to 2 IU/mL (for daily dosing). The prophylactic dosage of heparin was defined as 5,000 units given subcutaneously every 8 hours, and the therapeutic dose was defined as intravenous heparin titrated to an activated partial thromboplastin time between 70 and 110 seconds.

Variables in the full logistic model included anticoagulant dosage, age, ethnicity, diabetes, history of cancer or heart disease, hyperlipidemia, peak C-reactive protein level, and need for intensive care, mechanical ventilation, or use of antibiotics.

Motta and team found that the relative risk of in-hospital mortality was 2.3 times greater (P=0.04) in patients who received preemptive therapeutic-dose anticoagulation compared with standard prophylactic dosing on multivariate analysis, with 38.7 vs 14.4 deaths per 100 patients.

For the patient subgroup with elevated C-reactive protein levels, the researchers found no difference in the risk of mortality between those who received therapeutic versus prophylactic anticoagulation (adjusted risk ratio 1.0, 95% CI 0.2-4.5, P=0.97).

Most patients expired due to worsening oxygenation (71.8%) and acute respiratory failure with hypoxia. Other causes of death included anoxic brain injury due to hemorrhage (n=1), kidney dysfunction with inability to access hemodialysis port (n=1), and failure to thrive with encephalopathy (n=1). Just under two-thirds of patients (64.4%) elected to receive comfort measures only for end-of-life care.

The retrospective study design, lack of randomization, and no capture of mortality after the patients left the hospital were listed as study limitations. Unmeasured confounding and limited generalizability were additional limitations.

Source Reference: medRxiv 2020; DOI: 10.1101/2020.07.20.20147769

Study Highlights and Explanation of Findings:

A retrospective cohort study of hospitalized patients with COVID-19 showed an increase in in-hospital mortality following preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing.

These findings countered those of a larger observational study that suggested better survival with therapeutic anticoagulation in hospitalized COVID-19 patients, although others have suggested no effect.

It was possible that stronger thrombosis prevention is effective but just can't overcome competing risk of death from other disease processes in COVID-19, Motta's group suggested. "Regardless it does not seem from our analyses that therapeutic dosing of anticoagulation prevented overall disease progression," they noted.

However, "any interpretation other than acknowledging the need to study this prospectively in a randomized, controlled trial would be invalid," said Jason Katz, MD, director of cardiovascular critical care at the Duke University Health System in Durham, North Carolina, who was not involved with the study.

Aside from the small size, confounding and bias were also likely due to the "huge differences in patient characteristics between those who got prophylactic-dose anticoagulation and those that got full-dose anticoagulation," Katz pointed out.

Lack of data on bleeding events was another limitation, said Behnood Bikdeli, MD, of Brigham and Women's Hospital and Harvard University in Boston.

None of the studies done so far are able to really inform practice, he said. "What I do take out from this is the heterogeneity, the variability in the signals, and the effect sizes we keep seeing from these studies."

His group consensus, supported by the International Society on Thrombosis and Haemostasis and four other professional societies, recommended standard-dose prophylactic anticoagulation in most cases, despite noting a lack of data. The World Health Organization and NIH guidelines also suggest only using a higher-dose anticoagulant if there is a strong suspicion of thrombosis or in the context of a prospective study.

More than nine randomized controlled trials are underway to address questions of type and dose of antithrombotics for prophylaxis in COVID-19, Bikdeli noted.

The NIH has announced the ACTIV-4 set of adaptive platform clinical trials to evaluate safety and effectiveness of varying types of antithrombotics for adults diagnosed with COVID-19.

Well-designed studies that include enrollment of patients in areas with higher case loads should be able to deliver some answers in 2 to 3 months, Bikdeli predicted. "Because if you practice in the ICU, these questions come up for almost every single patient with COVID-19. We see abnormal coagulation parameters and we ask ourselves, 'Do we increase the dose, do we not increase the dose?'"

But with the real risk of clinically important, even fatal, bleeding(We should have had research decades ago that would instantly identify patients at risk for this bleeding. ), "it's not really something that you can do just by clinical gestalt," he said. "Once we have the data, yes, clinical experience would be important to make patient-by-patient decisions. But without that prospective, ideally randomized, data, we're just going blindly."

Last Updated August 05, 2020

Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College

Primary Source

medRxiv

Source Reference: Motta JK, et al "Clinical outcomes with the use of prophylactic versus therapeutic anticoagulation in COVID-19" medRxiv 2020; DOI: 10.1101/2020.07.20.20147769.

Secondary Source

MedPage Today

Source Reference: Phend C "Full-Dose Clot Prophylaxis for COVID-19 Tied to Mortality" 2020.

T.J. Samson Hospital(GLASGOW, Ky.) receives stroke award from American Heart, Stroke Association

Big fucking whoopee.

 

 But you tell us NOTHING ABOUT RESULTS. They remind us they 'care' about us 3 times but never tell us how many 100% recovered.

Three measurements will tell me if the stroke hospital is possibly not completely incompetent; DO YOU MEASURE ANYTHING?

1. tPA full recovery? Better than 12%?
2. 30 day deaths? Better than competitors?

3. rehab full recovery? Better than 10%?

 

You'll want to know results so call that hospital president(Whoever that is)
and demand to know what the RESULTS are; tPA efficacy, 30 day deaths, 100% recovery. Because there is no point in going to that hospital if they are not willing to publish results.

 The latest chest thumping here:

T.J. Samson Hospital(GLASGOW, Ky.) receives stroke award from American Heart, Stroke Association

GLASGOW, Ky. – T.J. Regional Health announced Monday that T.J. Samson Community Hospital has received recognition for its efforts to provide stroke patients with proper care, as outlined by the American Heart and Stroke Associations.

The award, Get With The Guidelines^®– Stroke Bronze Quality Achievement Award, recognizes the hospital’s commitment to ensuring stroke patients receive the most appropriate treatment according to nationally recognized, research-based guidelines based on the latest scientific evidence.

T.J. Samson Community Hospital earned the award by meeting specific quality achievement measures for the diagnosis and treatment of stroke patients at a set level for a designated period, a news release said.

These measures include evaluation of the proper use of medications and other stroke treatments aligned with the most up-to-date, evidence-based guidelines with the goal of speeding recovery and reducing death and disability for stroke patients. Before discharge, patients should also receive education on managing their health, get a follow-up visit scheduled, as well as other care transition interventions.

“T.J. Samson is dedicated to improving the quality of care for our stroke patients by implementing the American Heart Association’s Get With The Guidelines-Stroke initiative,” said Neil Thornbury, CEO of T.J. Regional Health. “The tools and resources provided help us track and measure our success in meeting evidenced-based clinical guidelines developed to improve patient outcomes.”(Well then, tell us what those recovery outcomes are.)

T.J. Samson Community Hospital received the designation of Acute Stroke Ready Hospital in September 2019, featuring a comprehensive system for rapid diagnosis and treatment of stroke patients admitted to the emergency department. After receiving this designation, many hospitals take more than a year to achieve the Bronze award. The Hospital will be eligible for the next tier, the Silver Achievement Award, if performance is sustained for the next 12 months, and for the Gold award for 24 months of sustained performance.

“We are pleased to recognize T.J. Samson Community Hospital for their commitment to stroke care,” said Lee H. Schwamm, M.D., national chairperson of the Quality Oversight Committee and Executive Vice Chair of Neurology, Director of Acute Stroke Services, Massachusetts General Hospital, Boston, Massachusetts. “Research has shown that hospitals adhering to clinical measures through the Get With The Guidelines^® quality improvement initiative can often see fewer readmissions and lower mortality rates.”

According to the American Heart Association/American Stroke Association, stroke is the No. 5 cause of death and a leading cause of adult disability in the United States. On average, someone in the U.S. suffers a stroke every 40 seconds and nearly 795,000 people suffer a new or recurrent stroke each year.

MUSC Florence(South Carolina) honored for its treatment of stroke patients

Big fucking whoopee.

 

 But you tell us NOTHING ABOUT RESULTS. They remind us they 'care' about us 3 times but never tell us how many 100% recovered.

Three measurements will tell me if the stroke hospital is possibly not completely incompetent; DO YOU MEASURE ANYTHING?

1. tPA full recovery? Better than 12%?
2. 30 day deaths? Better than competitors?

3. rehab full recovery? Better than 10%?

 

You'll want to know results so call that hospital president(Whoever that is)
and demand to know what the RESULTS are; tPA efficacy, 30 day deaths, 100% recovery. Because there is no point in going to that hospital if they are not willing to publish results.

 The latest chest thumping here:

MUSC Florence(South Carolina) honored for its treatment of stroke patients

FLORENCE, S.C. − MUSC Health Florence Medical Center announced it has received the American Heart Association/American Stroke Association’s Get With The Guidelines-Stroke Gold Plus & Target: Stroke Elite Honor Roll Quality Achievement Award.

The award recognizes the hospital’s commitment to ensuring that stroke patients receive the most appropriate treatment according to nationally recognized, research-based guidelines based on the latest scientific evidence.

MUSC Health Florence earned the award by meeting specific quality achievement measures for the diagnosis and treatment of stroke patients at a set level for a designated period. These measures include evaluation of the proper use of medications and other stroke treatments aligned with the most up-to-date, evidence-based guidelines with the goal of speeding recovery and reducing death and disability for stroke patients. Before discharge, patients should also receive education on managing their health, get a follow-up visit scheduled, as well as other care transition interventions.

“The American Heart Associations’ Get With The Guidelines-Stroke initiative is an important part of improving quality care for our patients,” said MUSC Health Florence Division Chief Executive Officer Vance Reynolds. “Because of this initiative, we have access to tools and resources ensuring the best outcomes and measuring our success in meeting evidence-based clinical guidelines.”

MUSC Health Florence Medical Center additionally received the Association’s Target: StrokeSM Elite Honor Roll award. To qualify for this recognition, hospitals must meet quality measures developed to reduce the time between the patient’s arrival at the hospital and treatment with the clot-buster tissue plasminogen activator, or tPA, the only drug approved by the U.S. Food and Drug Administration to treat ischemic stroke.

MUSC Health Florence Medical Center has also met specific scientific guidelines as a Primary Stroke Center, featuring a comprehensive system for rapid diagnosis and treatment of stroke patients admitted to the emergency department.

“It is fitting the Care Team at MUSC Health Florence be recognized for their outstanding efforts to take care of our patients who have a stroke,” said MUSC Health neurologist and medical director of the stroke center Dr. Elijah Owens. “Part of what distinguishes our Primary Stroke Center is our advanced diagnostic capabilities and treatments for routine brain attacks as well as complex stroke cases. Patients can be assured we are committed to the highest level of certain standards regarding diagnosis, prevention, treatment and rehabilitation with the ultimate goal of reducing the time between stroke onset and treatment.”

According to the American Heart Association/American Stroke Association, stroke is the No. 5 cause of death and a leading cause of adult disability in the United States. On average, someone in the U.S. suffers a stroke every 40 seconds and nearly 795,000 people suffer a new or recurrent stroke each year.

UAMS(University of Arkansas for Medical Sciences) Stroke Program Receives Two Awards for Excellence of Care

Big fucking whoopee.

 

 But you tell us NOTHING ABOUT RESULTS. They remind us they 'care' about us in the title but never tell us how many 100% recovered.

Three measurements will tell me if the stroke hospital is possibly not completely incompetent; DO YOU MEASURE ANYTHING?

1. tPA full recovery? Better than 12%?
2. 30 day deaths? Better than competitors?

3. rehab full recovery? Better than 10%?

 

You'll want to know results so call that hospital president(Whoever that is)
and demand to know what the RESULTS are; tPA efficacy, 30 day deaths, 100% recovery. Because there is no point in going to that hospital if they are not willing to publish results.

 The latest chest thumping here:

UAMS(University of Arkansas for Medical Sciences) Stroke Program Receives Two Awards for Excellence of Care

Excellence in treating stroke patients has earned the University of Arkansas for Medical Sciences (UAMS) Stroke Program two national awards.

The American Heart Association/American Stroke Association honored UAMS with the Get with the Guidelines Target: Stroke Honor Roll and Gold Plus Quality Achievement awards in June. The awards recognize the hospital’s commitment to ensuring stroke patients receive the most appropriate treatment according to nationally recognized, research-based guidelines based on the latest scientific evidence.

The Target: Stroke Honor Roll recognition acknowledges the program’s compliance with standards for quick and timely treatment of stroke. The Gold Plus status recognizes the program’s continued high performance by those measures for two or more consecutive years after receiving a Gold or Silver award. UAMS has maintained the Gold Plus status for six consecutive years.

“Our staff has worked very hard for many years first to achieve and then to continue to receive this recognition,” said Matthew Mitchell, M.N.Sc., R.N., director of the Stroke Program. “We want our patients to have the very best outcomes, and this recognition speaks to our efforts to follow the guidelines and standards of practice that ensure the best results for them.”

In 2018, UAMS Medical Center became the first and only health care provider in Arkansas to be certified as a Comprehensive Stroke Center by The Joint Commission. The Joint Commission is an independent, nonprofit organization that evaluates and accredits more than 20,000 health care organizations in the United States.

According to The Joint Commission, the certification is the most demanding accreditation and is designed for those hospitals that have the specific abilities to receive and treat the most complex stroke cases.

According to the American Heart Association/American Stroke Association, stroke is the fifth leading cause of death and a leading cause of adult disability in the United States. On average, someone in the U.S. suffers a stroke every 40 seconds and nearly 795,000 people suffer a new or recurrent stroke each year.

Blood-thinner with no bleeding side-effects is here

What is your doctor and hospital doing to follow this news? NOTHING?  Then go to the top and get the board of directors fired.

Blood-thinner with no bleeding side-effects is here

Date:

August 4, 2020

Source:

Ecole Polytechnique Fédérale de Lausanne

Summary:

Scientists have developed a synthetic blood-thinner that, unlike all others, doesn't cause bleeding side-effects. The highly potent, highly selective, and highly stable molecule can suppress thrombosis while letting blood clot normally following injury.

Share:

FULL STORY

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Patients who suffer from thrombosis, pulmonary embolism or stroke are usually put on drugs that help their blood flow more smoothly through their body. Occupying a large section of the drug market, anticoagulants, or "blood thinners" as they are popularly known, can keep blood clots from forming or getting bigger, and can therefore help with recover from heart defects or prevent further complications.

But there is a catch: blood thinners work by blocking enzymes that help to stop bleeding after an injury. Because of this, virtually every blood thinner available today can lead to serious, and even life-threatening bleeding following an injury.

The problem remained unsolved until a few years ago, when a study was carried out on mice that had been genetically modified to be deficient in an enzyme that normally helps blood clot. The enzyme is called "coagulation factor XII" (FXII), and the mice without the enzyme had a very reduced risk of thrombosis without having bleeding side-effects. The discovery triggered a race for FXII inhibitors.

Finally, a synthetic inhibitor

Participating in the race, the Laboratory of Therapeutic Proteins and Peptides of Professor Christian Heinis at EPFL has developed the first synthetic inhibitor of FXII. The inhibitor has high potency, high selectivity, and is highly stable, with a plasma half-life of over 120 hours. Published in Nature Communications, the study is the result of an extensive collaboration with three other labs in Switzerland and the US.

"The FXII inhibitor is a variation of a cyclic peptide that we identified in a pool of more than a billion different peptides, using a technique named phage display," says Heinis. The researchers then improved the inhibitor by painstakingly replacing several of its natural amino acids with synthetic ones. "This wasn't a quick task; it took over six year and two generations of PhD students and post-docs to complete."

With a potent FXII inhibitor in hand, Heinis's group wanted to evaluate it in actual disease models. To do this, they teamed up with experts in blood and disease-modeling at the University Hospital of Bern (Inselspital) and the University of Bern.

Working with the group of Professor Anne Angellillo-Scherrer (Inselspital), they showed that the inhibitor efficiently blocks coagulation in a thrombosis model without increasing the bleeding risk. Then they assessed the inhibitor's pharmacokinetic properties with the group of Professor Robert Rieben (University of Bern). "Our collaboration found that it is possible to achieve bleeding-free anti-coagulation with a synthetic inhibitor," says Heinis.

Artificial lungs

"The new FXII inhibitor is a promising candidate for safe thromboprotection in artificial lungs, which are used to bridge the time between lung failure and lung transplantation," says Heinis. "In these devices, contact of blood proteins with artificial surfaces such as the membrane of the oxygenator or tubing can cause blood clotting." Known as 'contact activation', this can lead to severe complications or even death and limits the use of artificial lungs for longer than a few days or weeks.

To test the effectiveness of the FXII inhibitor in artificial lungs, Heinis's group turned to Professor Keith Cook at Carnegie Mellon University (US), an expert for artificial lung system engineering. Cook's group tested the inhibitor in an artificial lung model, and found that it efficiently reduced blood clotting, all without any bleeding side-effects.

The only problem is that the inhibitor has a relatively short retention time in the body: it's too small and the kidneys would filter it out. In the context of artificial lungs, this would mean constant infusion, since suppressing blood clotting for several days, weeks or months requires a long circulation time.

But Heinis is optimistic: "We're fixing this; we're currently engineering variants of the FXII inhibitor with a longer retention time."

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Story Source:

Materials provided by Ecole Polytechnique Fédérale de Lausanne. Original written by Nik Papageorgiou. Note: Content may be edited for style and length.

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Journal Reference:

1. Jonas Wilbs, Xu-Dong Kong, Simon J. Middendorp, Raja Prince, Alida Cooke, Caitlin T. Demarest, Mai M. Abdelhafez, Kalliope Roberts, Nao Umei, Patrick Gonschorek, Christina Lamers, Kaycie Deyle, Robert Rieben, Keith E. Cook, Anne Angelillo-Scherrer, Christian Heinis. Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs. Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-17648-w

Poststroke Impairment and Recovery Are Predicted by Task-Specific Regionalization of Injury

Oh God, trying to justify the lazy stupidity of: 'All strokes are different, all stroke recoveries are different'. So fucking what? SOLVE THE RECOVERY PROBLEM, DON'T MAKE EXCUSES.  And the prediction you are trying to make is based upon  the failure of your existing guidelines to get survivors recovered. WHY SHOULD SURVIVORS ACCEPT SUCH INCOMPETENCE?

Dale Corbett should know better than this.

Poststroke Impairment and Recovery Are Predicted by Task-Specific Regionalization of Injury

Matthew S. Jeffers, Boris Touvykine, Allyson Ripley, Gillian Lahey, Anthony Carter, Numa Dancause and Dale Corbett

Journal of Neuroscience 29 July 2020, 40 (31) 6082-6097; DOI: https://doi.org/10.1523/JNEUROSCI.0057-20.2020

Abstract

Lesion size and location affect the magnitude of impairment and recovery following stroke, but the precise relationship between these variables and functional outcome is unknown. Herein, we systematically varied the size of strokes in motor cortex and surrounding regions to assess effects on impairment and recovery of function. Female Sprague Dawley rats (N = 64) were evaluated for skilled reaching, spontaneous limb use, and limb placement over a 7 week period after stroke. Exploration and reaching were also tested in a free ranging, more naturalistic, environment. MRI voxel-based analysis of injury volume and its likelihood of including the caudal forelimb area (CFA), rostral forelimb area (RFA), hindlimb (HL) cortex (based on intracranial microstimulation), or their bordering regions were related to both impairment and recovery. Severity of impairment on each task was best predicted by injury in unique regions: impaired reaching, by damage in voxels encompassing CFA/RFA; hindlimb placement, by damage in HL; and spontaneous forelimb use, by damage in CFA. An entirely different set of voxels predicted recovery of function: damage lateral to RFA reduced recovery of reaching, damage medial to HL reduced recovery of hindlimb placing, and damage lateral to CFA reduced recovery of spontaneous limb use. Precise lesion location is an important, but heretofore relatively neglected, prognostic factor in both preclinical and clinical stroke studies, especially those using region-specific therapies, such as transcranial magnetic stimulation.

SIGNIFICANCE STATEMENT By estimating lesion location relative to cortical motor representations, we established the relationship between individualized lesion location, and functional impairment and recovery in reaching/grasping, spontaneous limb use, and hindlimb placement during walking. We confirmed that stroke results in impairments to specific motor domains linked to the damaged cortical subregion and that damage encroaching on adjacent regions reduces the ability to recover from initial lesion-induced impairments. Each motor domain encompasses unique brain regions that are most associated with recovery and likely represent targets where beneficial reorganization is taking place. Future clinical trials should use individualized therapies (e.g., transcranial magnetic stimulation, intracerebral stem/progenitor cells) that consider precise lesion location and the specific functional impairments of each subject since these variables can markedly affect therapeutic efficacy.

Smoking or vaping cannabis could cause strokes, heart attacks

Oh my god, what an alarmist headline, when you actually read the research they have in no way  proven that cannabis is the problem rather than the smoking or vaping.

My 13 reasons for marijuana use post-stroke.  

Don't follow me, I'm not medically trained and I don't have a Dr. in front of my name.

Smoking or vaping cannabis could cause strokes, heart attacks

By

Nicole Lyn Pesce

37

American Heart Association warns against weed, calls on the government to allow more research

The American Heart Association warns against smoking or inhaling cannabis over its reported cardiovascular risks.

American Heart Association

Some studies are sending dreams of cannabis being a cure-all up in smoke.

The American Heart Association is warning that marijuana use shows “substantial risks” and “no benefit” in cardiovascular health, and its deputy chief science and medical officer is recommending that people “not smoke or vape any substance, including cannabis products, because of the potential harm to the heart, lungs and blood vessels.”

Marijuana contains the psychoactive chemical THC (which gives users the “high”), as well as more than 100 compounds (cannabinoids, such as the popular cannabidiol, or CBD ) chemically related to THC that are still not entirely understood. Studies suggest that they inhibit some enzymes in the body that can affect the way we metabolize certain heart disease medications, such as cholesterol-lowering statins and blood-thinning warfarin, which skews what’s considered a safe dosage.

So in a scientific paper published Wednesday, the American Heart Association (AHA) cites a growing crop of observational studies suggesting that cannabis use is linked to an increased risk of heart attacks, irregular heartbeats (atrial fibrillation, or AFib) and heart failure; a nearly 2.5 times higher risk of strokes; chest pain or angina; and high blood pressure.

Some 2 million Americans with heart disease currently use marijuana or have used it in the past, according to a recent report in the Journal of the American College of Cardiology, which notes that more than 39 million U.S. adults have used the drug in the past year.

What’s more, the AHA reports that THC appears to stimulate the body’s “fight or flight” response, which can trigger a higher heart rate, a greater demand for oxygen by the heart, higher blood pressure while laying down, and dysfunction within the walls of the arteries. The AHA also reports that states that have legalized cannabis have seen an increase in hospitalizations and ER visits for heart attacks.(Correlation, NOT CAUSE)

The heart-health body called out inhaling combustible cannabis, in particular, as smoking and inhaling marijuana (regardless of THC potency) has been shown to increase the concentrations of carbon monoxide and tar in the body similar to the effects of smoking a tobacco cigarette. “People who use cannabis need to know there are potentially serious health risks in smoking or vaping it, just like tobacco smoke,” said Dr. Rose Marie Robertson, the deputy chief science and medical officer for the American Heart Association, in a statement.

Yet many Americans assume smoking or vaping marijuana isn’t as dangerous as smoking cigarettes, even though smoking marijuana usually involves taking a large hit and holding it in, as opposed to the more frequent, smaller puffs used for smoking cigarettes. Therefore, smoking cannabis may deposit as much — if not more — of the chemicals in the lungs as when people smoke cigarettes. And vaping has been shown to carry health risks, especially after vaping-related lung illness sickened hundreds of Americans last year.

Edibles aren’t entirely in the clear, however, as it’s all-too-easy to accidentally ingest too much of the drug. A Canadian man with pre-existing heart disease had a heart attack last year, an hour after eating most of a lollipop laced with 90 milligrams of THC. He had taken it to treat his arthritis pain so that he could sleep better. Researchers noted that people typically inhale 7 milligrams while smoking a single marijuana joint.

Related:‘CBD has the potential to harm you,’ FDA warns consumers

But then again, research has suggested that CBD, which does not intoxicate users, has been associated with lower blood pressure, lower heart rate and reduced seizures, which are all good things.

CBD also shows some promise for treating anxiety disorders. And cannabis has been found to treat pain, nausea and vomiting, anxiety and loss of appetite caused by cancer or the side effects of cancer therapies. Indeed, medical marijuana is legal in 33 U.S. states and Washington, D.C., where it is prescribed for pain management, anxiety and depression.

The problem is, research into cannabis’ complex relationship with the cardiovascular system remains in the weeds because it’s illegal under U.S. federal law. Marijuana is classified as a Schedule I drug by the U.S. Drug Enforcement Agency (DEA), which limits scientists from studying it, or even getting access to enough high-quality product to study it.

“We urgently need carefully designed, prospective short- and long-term studies regarding cannabis use and cardiovascular safety as it becomes increasingly available and more widely used,” said Robert L. Page II, chair of the AHA writing group for the statement. “The public needs fact-based, valid scientific information about cannabis’s effect on the heart and blood vessels.”

Related:FDA releases guidelines for cannabis-related research, but CBD will have to wait

The cannabis industry agrees on the need for more research, although it questioned the American Heart Association’s more dire health claims.

“The cannabis industry is on the same page as the American Heart Association in calling for more research for many reasons, including the dearth of definitive evidence supporting their claims,” Morgan Fox, the media relations director for the National Cannabis Industry Association, told MarketWatch by email.

“Cannabis — like almost any other psychoactive substances — can have harms associated with its consumption, but it is clear that the harms associated with prohibition and keeping the cannabis market underground and unregulated are far worse for the consumer and society,” he added, while calling cannabis “objectively safer” than many other legal substances. “Regulation is necessary to facilitate the research and education that are key to helping adults make informed decisions about whether and how to consume cannabis.”

Cannabis use has become more acceptable in American society, as 11 states and Washington, D.C. have legalized recreational marijuana. And there’s money to be made here. Barclays estimates that the U.S. cannabis market would be $28 billion if it was legalized by the federal government today, reaching $41 billion by 2028, while the CBD market is expected to hit $2.1 billion this year, as MarketWatch previously reported.

Changes in Structural Integrity Are Correlated With Motor and Functional Recovery After Post-stroke Rehabilitation

I saw nothing in here that suggested any way to improve structural integrity to help with recovery. Just describing  something, so useless.

Changes in Structural Integrity Are Correlated With Motor and Functional Recovery After Post-stroke Rehabilitation

Published 2015
 Yang-teng Fan a,1,

Keh-chung Lin a,b,1,

Ho-ling Liu c,

Yao-liang Chen d,

and Ching-yi Wu e,f,∗
a School of Occupational Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan
b  Division of Occupational Therapy, Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Taipei, Taiwan
c Department of Imaging Physics, Division of Diagnostic Imaging, The University of Texas MD AndersonCancer Center, Houston, TX, USA
d MRI Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
e Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, College of Medicine,Chang Gung University, Taoyuan, Taiwan
f  Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan

Abstract

.
Purpose:
Diffusion tensorimaging(DTI) studies indicate the structural integrity of the ipsilesional corticospinal tract(CST) and the transcallosal motor tract, which are closely linked to stroke recovery. However, the individual contribution of these 2 fiberson different levels of outcomes remains unclear. Here, we used DTI tractography to investigate whether structural changes of the ipsilesional CST and the transcallosal motor tracts associate with motor and functional recovery after stroke rehabilitation.
Methods:
 Ten participants with post-acute stroke underwent the Fugl-Meyer Assessment (FMA), the Wolf Motor Function Test(WMFT), the Functional Independence Measure (FIM), and DTI before and after bilateral robotic training.
Results:
 All participants had marked improvements in motor performance, functional use of the affected arm, and independence in daily activities. Increased fractional anisotropy (FA) in the ipsilesional CST and the transcallosal motor tracts was noted from pre-treatment to the end of treatment. Participants with higher pre-to-post differences in FA values of the transcallosal motor tracts had greater gains in the WMFT and the FIM scores. A greater improvement on the FMA was coupled with increased FAchanges along the ipsilesional CST.
Conclusions:
These findings suggest 2 different structural indicators for post stroke recovery separately at the impairment based and function based levels.

Indirect structural connectivity identifies changes in brain networks after stroke

Useless. Identifies a problem, OFFERS NO SOLUTION!

Indirect structural connectivity identifies changes in brain networks after stroke

Mr. Miguel Sotelo

,

Dr. Benjamin Kalinosky

,

Dr. Karin Goodfriend

,

Dr. Allison Hyngstrom

, and

Dr. Brian Schmit

Published Online:31 Jul 2020https://doi.org/10.1089/brain.2019.0725

Abstract

Background / Purpose:
The purpose of this study was 1) to identify changes in structural connectivity after stroke and 2) to relate changes in indirect connectivity to post-stroke impairment.
Methods:
A novel measure of indirect connectivity was implemented to assess the impact of stroke on brain connectivity. Probabilistic tractography was performed on 13 chronic stroke and 16 control participants to estimate connectivity between gray matter regions. The Fugl-Meyer assessment of motor impairment was measured for stroke participants. Network measures of direct and indirect connectivity were calculated, and these measures were linearly combined with measures of white matter integrity to predict motor impairment.
Results:
We found significantly reduced indirect connectivity in the frontal and parietal lobes, ipsilesional subcortical regions and bilateral cerebellum after stroke. When added to the regression analysis, the volume of gray matter with reduced indirect connectivity significantly improved the correlation between image parameters and upper extremity motor impairment (R2=0.71, p<0.05).
 Conclusion:
This study provides evidence of changes in indirect connectivity in regions remote from the lesion, particularly in the cerebellum and regions in the fronto-parietal cortices, and these changes correlate with upper extremity motor impairment. These results highlight the value of using measures of indirect connectivity to identify the effect of stroke on brain networks.