Warfarina vs heparina para AVC embólico

Anticoagulation After Cardioembolic Stroke
To Bridge or Not to Bridge?
Hen Hallevi, MD; Karen C. Albright, DO, MPH; Sheryl Martin-Schild, MD, PhD; Andrew D. Barreto, MD; Sean I. Savitz, MD; Miguel A. Escobar, MD; Nicole R. Gonzales, MD; Elizabeth A. Noser, MD; Kachi Illoh, MD; James C. Grotta, MD
Arch Neurol. 2008;65(9):1169-1173. Published online July 14, 2008 (doi:10.1001/archneur.65.9.noc70105).
Background Most patients with cardioembolic stroke require long-term anticoagulation. Still, uncertainty exists regarding the best mode of starting long-term anticoagulation.
Design, Setting, and Patients We conducted a retrospective review of all patients with cardioembolic stroke admitted to our center from April 1, 2004, to June 30, 2006, and not treated with tissue plasminogen activator. Patients were grouped by treatment: no treatment, aspirin only, aspirin followed by warfarin sodium, intravenous heparin sodium in the acute phase followed by warfarin (heparin bridging), and full-dose enoxaparin sodium combined with warfarin (enoxaparin bridging). Outcome measures and adverse events were collected prospectively. Laboratory values were captured from the records.
Main Outcome Measures Symptomatic hemorrhagic transformation, stroke progression, and discharge modified Rankin Scale score.
Results Two hundred four patients were analyzed. Recurrent stroke occurred in 2 patients (1%). Progressive stroke was the most frequent serious adverse event, seen in 11 patients (5%). Hemorrhagic transformation occurred in a bimodal distribution—an early benign hemorrhagic transformation and a late symptomatic hemorrhagic transformation. All of the symptomatic hemorrhagic transformation cases were in the enoxaparin bridging group (10%) (P = .003). Systemic bleeding occurred in 2 patients (1%) and was associated with heparin bridging (P = .04).
Conclusions Anticoagulation of patients with cardioembolic stroke can be safely started with warfarin shortly after stroke. Heparin bridging and enoxaparin bridging increase the risk for serious bleeding.
Author Affiliations: Department of Neurology, University of Texas at Houston Medical School (Drs Hallevi, Martin-Schild, Barreto, Savitz, Gonzales, Noser, Illoh, and Grotta) and Department of Hematology (Dr Escobar), University of Texas Health Science Center at Houston; and Department of Neuroscience, University of California, San Diego (Dr Albright).

Tríplice terapia antiplaquetária aumenta risco na prevenção secundária do AVC

A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility
Nikola Sprigg, Laura J. Gray, Tim England, Mark R. Willmot, Lian Zhao, Gillian M. Sare, Philip M. W. Bath*
Abstract
Background
Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke.
Methodology/Principal Findings
A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01).
Conclusions/Significance
Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy.

Antipsicóticos e risco de AVC

Study indicates antipsychotic medications may increase stroke risk.The BBC (8/28) reported that "all forms of antipsychotics" may increase the risk of stroke, according to a study published online in the Aug. 29 issue of the BMJ. Ian Douglas, M.D., of the London School of Hygiene and Tropical Medicine in the U.K., and colleagues, "identified 6,700 patients from a" general-practitioner "database, all with an average age of 80, and concluded that there was more than a tripling of risk for dementia patients taking any sort of anti-psychotic drug." But, "patients without dementia taking any sort of antipsychotic" also "had a 40 percent increase in risk." Therefore, the authors "repeated the recommendation that patients with dementia should not be prescribed these drugs." "The risk for stroke was slightly higher for people taking the newer atypical antipsychotics, compared with people taking the older typical antipsychotics," HealthDay (8/28, Reinberg) added. "Atypical antipsychotics include drugs such as Abilify (aripiprazole), Clozaril (clozapine), and Zyprexa (olanzapine). Typical antipsychotics include Thorazine (chlorpromazine), Haldol (haloperidol), and Clopixol (zuclopenthixol)." The authors, however, did not examine "the potential mechanisms associated with antipsychotics that cause stroke, or why the risk appears higher with atypical antipsychotics."

Profess: não inferioridade de antiplaquetários

PROFESS Trial Published: Combination Therapy Falls Short of Noninferiority vs Clopidogrel
Susan Jeffrey
August 28, 2008 — In the largest secondary stroke-prevention trial to date, the combination of aspirin and extended-release (ER) dipyridamole (Aggrenox, Boehringer Ingelheim) did not meet prespecified criteria for noninferiority vs clopidogrel (Plavix/Iscover, Sanofi-Aventis/Bristol-Myers Squibb), but rates of recurrent stroke, the primary outcome, were similar between the groups.
"Therefore, the study does not show that either aspirin plus extended-release dipyridamole or clopidogrel is superior to the other in the prevention of stroke," the investigators, with first author Ralph L. Sacco, MD, from the Miller School of Medicine at the University of Miami, in Florida, conclude.
"These findings provide additional safety and efficacy data physicians need in making individual treatment decisions for prevention of recurrent stroke or the combined end point of stroke, myocardial infarction [MI], or death from vascular causes in their patients with stroke," they write.
In a factorial design, the trial also examined the effect of early blood pressure lowering after a stroke using telmisartan (Micardis, Boehringer Ingelheim) vs placebo and found no benefit of the addition of the angiotensin-receptor blocker (ARB) in prevention of stroke recurrence, major cardiovascular events, or diabetes, at least during the 2.5 years of follow-up in this study.
The results are published online as 2 papers August 27 in the New England Journal of Medicine. The findings were previously presented at the 17th European Stroke Conference, in Nice, France, and reported by Medscape Neurology & Neurosurgery at that time.
Factorial Design
The PROFESS trial included 20,332 patients from 695 sites in 35 countries. All had had a noncardioembolic ischemic stroke within the previous 120 days. They were randomized in a factorial design to receive aspirin (25 mg) plus ER dipyridamole (200 mg) twice daily or clopidogrel (75 mg) once daily. Subjects were then again randomized to receive either 80 mg per day of telmisartan or placebo.
Current guidelines in Europe and the United States recommend that for antiplatelet therapy after a stroke, aspirin, aspirin plus dipyridamole, and clopidogrel are options for prevention of stroke recurrence, but there is no recommendation for the use of 1 of these agents over the others. Direct comparison of aspirin alone vs aspirin and dipyridamole in the European and Australian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) and the European Stroke Prevention Study 2 (ESPS2) had shown the combination to be more effective than aspirin alone without increasing major bleeding. The PROFESS trial aimed to provide information on a direct comparison of the combination vs clopidogrel.
The planned antiplatelet comparison used a sequential analysis of noninferiority first, then superiority, the researchers noted. The margin chosen for noninferiority was 1.075, or a 7.5% noninferiority difference.
In the end, the comparison for the primary outcome of recurrent stroke did not meet this predefined criterion for noninferiority, although the number of recurrent strokes was similar between the groups
PROFESS: Primary Outcome for Comparison of Aspirin Plus Extended-Release Dipyridamole vs Clopidogrel
End Point
Aspirin + ER-Dipyridamole
Clopidogrel
Hazard Ratio (95% CI)
P
Stroke recurrence, n (%)
915 (9.0)
898 (8.8)
1.01 (0.92 – 1.11)
.783
The secondary outcome, a composite of stroke, MI, and vascular death, was identical between groups, they note. Other end points, including deaths and MI, were not statistically different between groups, with the exception of new or worsening heart failure, which was significantly less frequent in the combination group.
Major hemorrhagic events were increased with the combination vs clopidogrel; intracranial hemorrhage (ICH), including 128 hemorrhagic strokes counted in the primary outcome, was significantly higher with the combination. There were no significant differences between the 2 groups in the frequency of death, any hemorrhagic event (major or minor), or thrombotic thrombocytopenia purpura or neutropenia.
PROFESS: Major Hemorrhagic Events
Event
Aspirin + ER-Dipyridamole
Clopidogrel
Hazard Ratio (95% CI)
Major hemorrhagic events, n (%)
419 (4.1)
365 (3.6)
1.15 (1.00 – 1.32)
ICH
147 (1.4)
103 (1.0)
1.42 (1.11 – 1.83)
Despite the increase in bleeds, the net risk for recurrent stroke or major hemorrhagic event was similar between the groups.
PROFESS: Benefit/Risk Analysis
End Point
Aspirin + ER-Dipyridamole
Clopidogrel
Hazard Ratio (95% CI)
P
Recurrent stroke or major hemorrhagic event, n (%)
1194 (11.7)
1156 (11.4)
1.03 (0.95 – 1.11)
.504
Adverse events leading to permanent discontinuation were increased with the combination (16.4%) vs clopidogrel (10.6%). Headache was more frequent with the combination, leading to permanent discontinuation in 5.9% of the patients on combination therapy vs 0.9% on clopidogrel.
Dr. Sacco told Medscape Neurology & Neurosurgery that this study provides more evidence that clopidogrel is as effective as ER dipyridamole and aspirin in terms of reducing recurrent stroke.
"How we choose between the 2 agents is still going to be up to clinicians," he said. "For those patients with more cardiac disease, some of us may choose clopidogrel more often, and for others we still have extended-release dipyridamole as an option."
Telmisartan vs Placebo
In a separate paper, the PROFESS researchers, with lead author Salim Yusuf, MD, from McMaster University, in Hamilton, Ontario, published results of the telmisartan-placebo comparison.
Previous studies, including the Heart Outcomes Prevention Evaluation (HOPE) and the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), had shown a benefit associated with using an angiotensin-converting enzyme (ACE) inhibitor initiated late after stroke, with or without a large reduction in blood pressure. In this trial, the PROFESS researchers investigated whether using a blocker of the renin-angiotensin system, telmisartan, initiated early after a stroke, would reduce recurrent stroke.
Despite a mean blood pressure difference between the groups of 3.8/2.0 mm Hg in favor of telmisartan, there was no difference between groups on the primary end point of recurrent stroke, on secondary outcomes of a composite of major cardiovascular events (death from cardiovascular causes, recurrent stroke, MI, or new or worsening heart failure), or in new-onset diabetes.
PROFESS: Primary and Secondary Outcomes with Telmisartan vs Placebo
End Point
Telmisartan
Placebo
Hazard Ratio (95% CI)
P
Recurrent stroke, n (%)
880 (8.7)
934 (9.2)
0.95 (0.86 – 1.04)
.23
Major CV events, n (%)
1367 (13.5)
1463 (14.4)
0.94 (0.87 – 1.01)
.11
New-onset diabetes (%)
1.7
2.1
0.82 (0.65 – 1.04)
.10
Subsequent analyses suggested there may have been an effect by time, Dr. Yusuf noted when he presented these results in Nice, and the researchers speculate that the trial may have been too short to see a benefit with treatment. Suboptimal adherence in the treatment group, as well as competing use of other blood pressure–lowering agents, reduced the blood pressure differential between the groups, "which hurt our power," he said.
"What we need are longer trials, but large trials, with greater blood pressure lowering," Dr. Yusuf concluded.
A third factorial analysis of the PROFESS data, looking for any neuroprotective effects of dipyridamole, aspirin, or the ARB telmisartan in those patients who did have a recurrent stroke, was also presented at the European Stroke Conference by first author Hans-Christof Diener, MD, from the University of Duisberg-Essen, in Essen, Germany. Results of that analysis, that at least in the preliminary analysis presented in Nice showed no evidence of any such neuroprotective effects, will be published separately

Tibolona na pós-menopausa

The Effects of Tibolone in Older Postmenopausal Women
Steven R. Cummings, M.D., Bruce Ettinger, M.D., Pierre D. Delmas, M.D., Ph.D., Peter Kenemans, M.D., Ph.D., Victoria Stathopoulos, Ph.D., Pierre Verweij, Ph.D., Mirjam Mol-Arts, M.D., Lenus Kloosterboer, Ph.D., Lori Mosca, M.D., Ph.D., M.P.H., Claus Christiansen, M.D., John Bilezikian, M.D., Eduardo Mario Kerzberg, M.D., Susan Johnson, M.D., Jose Zanchetta, M.D., Diederich E. Grobbee, M.D., Ph.D., Wilfried Seifert, Ph.D., Richard Eastell, M.D., for the LIFT Trial Investigators

ABSTRACT
Background Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain.
Methods In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of –2.5 or less at the hip or spine or a T score of –2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels.
Results During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups.
Conclusions Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis.