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The Hospitalist and Stroke Prevention
Prevention has the greatest potential to reduce the societal burden from stroke.1 Several therapies that specifically target the underlying atherosclerotic disease process have been shown in clinical trials to markedly lower the risk of recurrent vascular events including stroke.2 However, there is great variability in how clinical trial data are implemented in clinical practice for ischemic stroke prevention.35 This has led to a knowledge‐implementation‐practice gap, possibly because of the limited awareness of the scientific evidence supporting various treatments, as well as the lack of a systematic approach to hospital stroke care.3 Our review discusses the evidence for reducing vascular risk after ischemic stroke and successful models of systematic interventions initiated during stroke hospitalization, with the goal of narrowing the stroke hospitalization evidencepractice gap.
Societal Burden
Stroke is the third‐leading cause of death in the United States and the leading cause of serious long‐term disability.6 Approximately 700,000 Americans have a new stroke or recurrent strokes every year, whereas nearly 5 million live with the consequences of stroke; nearly all stroke survivors (90%) have some residual functional deficit, and approximately 40% experience moderate to severe impairment.6 Stroke mortality is substantial, with a 30‐day case fatality rate after first stroke (of any cause) of about 25%.7, 8 Indeed, four‐fifths of patients do not survive for 10 years after stroke, and approximately one‐third of all case fatalities occur in the first year after a stroke.8 The estimated economic impact in 2006, US$57.9 billion, further underscores the substantial mortality and morbidity of stroke.6 Given the limited options for acute stroke therapies,9 stroke prevention remains an important therapeutic goal, especially because fewer than 5% of acute stroke patients in the United States currently receive the only Food and Drug Administrationapproved treatmentintravenous tissue plasminogen activator.10 It is obvious that additional strategies are urgently needed to reduce the devastating consequences of stroke.
Why Involve the Hospitalist?
The Hospitalist system in the United States is rapidly growing.11 Tthe Society of Hospital Medicine projects that by 2010 there will be approximately 30,000 hospitalists in the United States.11 A member census conducted by the American Academy of Neurology in 2000 found 13,500 practicing neurologists, most of whom are concentrated in urban and metropolitan areas.12 As such, with more than 700,000 strokes occurring each year,6 most stroke patients in the United States will not be seen or evaluated by a neurologist. Indeed, one study indicated that only 11.3% of stroke patients are attended exclusively by a neurologist.13 Furthermore, it is not uncommon for stroke patients to have numerous other medical issues that require attention and multidisciplinary care coordination during the hospital stay, an area where hospitalists excel. Conceivably, the ability to promptly identify and treat these non‐neurological comorbidities, which account for at least 30% of the deaths from acute ischemic stroke,14 could go a long way toward improving stroke outcomes.
Hospitalists are in the forefront of developing strategies for improving the quality of acute care and patient satisfaction, reducing medical errors, and focusing on efficient resource utilization. Translating evidence‐based strategies for acute stroke care into actual practice is a mechanism for improving the quality of care, ensuring that basic care does not deviate from provider to provider or from day to day (weekdays compared to weekend days/holidays) while at the same time allowing for the individualization of care appropriate to a patient's unique needs.15 After the acute treatment of stroke or TIA, additional measures must be initiated as soon as it is safe to do so in order to begin the process of limiting stroke progression and preventing recurrence. Secondary prevention measures require a coordinated transition in order to ensure continuation of care and follow‐up as needed. After a thorough risk assessment is complete, hospitalists will need to consider a 3‐pronged approach to secondary prevention that follows the national guidelines described above: pharmacotherapy, behavior modification, and, in some cases, surgical intervention.
Secondary Stroke
Secondary or recurrent strokes are strokes that occur after a first stroke or TIA,2 and the single biggest risk factor for having a stroke is already having had one.2 Because hospitalists generally see patients after ischemic cerebrovascular events have already happened, their opportunities to intervene are mostly geared toward reducing the risk of secondary stroke (beyond enhancing the prevention of complications from the index event). Recent community‐based data indicate that the short‐term risk of secondary stroke is high.16, 17 After a minor stroke or TIA, the risk of recurrent stroke or TIA increases over time8%‐12% within 7 days, 12%‐15% within 30 days, and 17%‐19% within 90 days.18 In the largest study of short‐term risk following TIA,19 there was an 11% risk of stroke (51% of which occurred in the 48 hours after TIA), an 13% risk of TIA, and a 25% risk of any adverse event within 90 days of the TIA.
Overall, the risk of a second cerebrovascular event is highest in the first year after a stroke/TIA (12%), declining to about 5% annually thereafter.7 The effects of secondary stroke are more devastating than those of the primary stroke: the 30‐day fatality rate after a first recurrent stroke is almost double that after the first‐ever stroke (41% versus 22%).20 The pathological factors that lead to TIA and stroke, such as platelet aggregation and subsequent thrombosis or the systolic stroke of blood against stenotic carotid plaques, are one and the same. As such, the short‐ and long‐term risks of recurrent events after both first stroke or first TIA necessitate investigation into a patient's vascular risk and early initiation of appropriate stroke prevention strategies.21
Cross Risk
Because the atherothrombotic disease process is systemic in nature with a variety of manifestations, stroke patients with atherosclerosis frequently have coexistent coronary artery disease and peripheral artery disease,22 and as such, are at risk for vascular events emanating from any of these beds in addition to that of the cervicocephalic arterial tree.23, 24 For instance, in a study of individuals in a long‐term care facility, among the patients with ischemic stroke, 56% had overlapping coronary artery disease, 28% had peripheral artery disease,25 and 38% of the patients had at least 2 manifestations of their atherosclerotic disease. The take‐home message here is that hospitalists also have the opportunity while treating patients hospitalized following stroke to prevent other vascular events by identifying and treating stroke patients who have systemic atherosclerosis.
Risk Factors
The first step in any approach to stroke prevention is the identification of predisposing risk factors. Several of the known biological and lifestyle risk factors associated with cerebrovascular disease were identified decades ago from large longitudinal studies.2 Certain stroke risk factors are nonmodifiable and therefore cannot be the target of intervention. 26 Treatment of the various stroke risk factors could have a substantial impact on reducing the burden of stroke. Table 1 shows the number needed to treat to prevent one stroke per year by modification of the individual stroke risk factor.
| Treatment | Relative risk reduction | Number needed to treat (1 stroke/year) |
|---|---|---|
| ||
| Antihypertensives | 28% | 51 |
| Statins | 25% | 57 |
| Aspirin | 28% | 77 |
| Smoking cessation | 33% | 43 |
| Carotid endarterectomy | 44% | 26 |
Guidelines for Secondary Stroke Prevention
Several organizations have published guidelines for the prevention of secondary stroke based on clinical evidence and expert consensus. Key guidelines include those published by the American Stroke Association (ASA),2 American College of Chest Physicians (ACCP),27 and the National Stroke Association. Although these guidelines are broadaddressing many components of stroke prevention and careeach contains recommendations specifically applicable to secondary prevention in most stroke patients who the hospitalist will encounter. Some provide hospital‐based guidelines that focus on care protocols and systems processes (ie, ASA Stroke Systems Guidelines), whereas others are therapy‐based guidelines (i.e, ACCP Guidelines on Antithrombotic Therapy for Ischemic Stroke). In the next few sections, we discuss common risk factors for and causes of secondary stroke and the prevailing guideline recommendations for modifying them. Discussion of the management of rare causes of ischemic stroke such as arterial dissection, vasculitis, patent foramen ovale, and so forth is beyond the scope of this article.
Hypertension, Dyslipidemia, and Diabetes
Table 2 shows the current national guideline recommendations for the management of premier vascular risk factorshypertension, dyslipidemia, and diabetesin ischemic stroke and TIA patients.2 Antihypertensive therapy is recommended for the prevention of secondary stroke and other vascular events in patients who have experienced an ischemic stroke or TIA and are beyond the hyperacute period.28, 29 Such treatment should be considered for all ischemic stroke and TIA patients regardless of history of hypertension.28 Although available data support the use of diuretics and the combination of diuretics plus an angiotensin‐converting enzyme inhibitor,28, 30 selection of specific medications should be individualized according to a patient's comorbid conditions.29 It is also important to note that despite the proven benefit of beta blockers in the secondary prevention of recurrent cardiac events, current evidence shows no clear benefit from the use of beta blockers in the prevention of stroke.29, 31
| Risk Factor | Recommendation |
|---|---|
| |
| Hypertension | Antihypertensive beyond hyperacute stroke period60 |
| Data support diuretic or diuretic + ACEI,2830 but individualize based on patient characteristics | |
| Antihypertensive in all patients regardless of history of hypertension28 | |
| Aim for average reduction of 10/5 mm HG or blood pressure < 120/80 mm Hg28 | |
| Encourage reduced intake of dietary salt | |
| Dyslipidemia | Statin for LDL‐C goal < 100 mg/dL in those with CAD or symptomatic atherosclerosis33, 34 |
| Target LDL‐C < 70 mg/dL for very high‐risk persons61 | |
| Statin for stroke or TIA because of atherosclerosis regardless of LDL‐C level33, 34 | |
| Niacin or gemfibrozil for patients with low HDL‐C62, 63 | |
| Diabetes | ACEIs and ARBs should be first‐choice blood pressure drugs37, 38a |
| Glucose control to near normoglycemic levels39 | |
| Target glycosylated hemoglobin 7%64 | |
For ischemic cerebrovascular disease patients with dyslipidemia or symptomatic atherosclerosis, cholesterol management should be according to the current Adult Treatment Panel (ATP) guidelines.32 Statins should be the first‐line treatment.33, 34 Ischemic stroke or TIA patients whose underlying stroke mechanism is presumed to be atherosclerosis should be considered for statin therapy even if they have normal cholesterol levels and no evidence of atherosclerosis.33, 34 The recent Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study was the first study to specifically investigate the effect of statins in patients with a prior stroke but with normal cholesterol levels and no evidence of coronary heart disease. It found that treatment with atorvastatin 80 mg/day (vs. placebo) was associated with a 16% reduction in relative risk of recurrent stroke.34
The care of an ischemic stroke or TIA patient who has diabetes warrants more rigorous control of blood pressure and lipids.35, 36 Such patients usually require more than one antihypertensive drug. ACEIs and angiotensin receptor blockers (ARBs) are more effective in reducing the progression of renal disease and are the recommended first‐choice medications for these patients.37, 38 The target for glucose control should be reaching near‐normoglycemic levels.39
Large‐Artery Atherosclerosis
In selected at‐risk stroke patients, surgical techniques (eg, carotid endarterectomy [CEA], carotid angioplasty and/or stenting [CAS]) may reduce the rate of recurrent stroke.4044 For patients who have had ischemic cerebrovascular events in the preceding 6 months and who have ipsilateral severe (70%‐99%) cervical carotid artery stenosis, CEA done by a surgeon is recommended; it has a perioperative morbidity and mortality of less than 6%.40 For those with ipsilateral moderate (50%‐69%) cervical carotid stenosis, CEA should be considered, and whether to operate should be decided on the basis of the patient's age, sex, comorbidities, and severity of initial symptoms.41 Analyses of endarterectomy trials indicated that the benefit from CEA is greatest if performed within 2 weeks of a patient's last ischemic event, the advantage it confers rapidly falling with increasing delay.45 From the hospitalist's standpoint, it is of prime importance to ensure that patients admitted to the hospital with a TIA or ischemic stroke are not discharged before it has been established whether have severe carotid stenosis that requires a revascularization procedure. If carotid stenosis is less than 50%, CEA is not recommended.41
A newer, less invasive form of carotid artery revascularization is CAS,46 which is performed by operators with established periprocedural morbidity and mortality rates of 4%‐6% and may be considered in those with:
-
Symptomatic severe stenosis (>70%) that is difficult to access surgically.2
-
Medical issues that greatly increase the risks of surgery, such as clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal nerve palsy, radiation‐induced stenosis or restenosis after carotid endarterectomy, and more than 80 years old.43
Angioplasty and/or stenting may also be considered when patients with symptomatic extracranial vertebral stenosis are having symptoms despite optimal medical risk factor treatments.2 Among those with hemodynamically significant stenosis of the major intracranial vasculature (basilar, middle cerebrals, distal carotids, and vertebrals) experiencing symptoms despite optimal medical risk factor treatments, angioplasty and/or stenting is considered experimental.2
The degree of arterial stenosis can be assessed by ultrasound, magnetic resonance angiogram (MRA), computed tomography angiogram (CTA), and conventional catheter angiogram, the last of which remains the gold standard. A carotid ultrasound performed at a certified vascular laboratory or by an experienced radiology technologist that shows less than 50% stenosis need not be followed up with another neuroimaging test. Generally, MRA tends to overestimate the degree of arterial stenosis but is a useful screening tool. In the event that an MRA reveals more than 50% stenosis, another diagnostic modality such as a carotid duplex, CTA, or conventional catheter angiogram should be performed to confirm this finding.
Antithrombotic Treatment
Cardioembolic Stroke Mechanism
Although it can sometimes be difficult to determine the precise mechanism underlying a patient's stroke or TIA, those who have a high‐risk source of cardiogenic embolism should generally be treated with anticoagulant medications to prevent recurrence.2 Among ischemic cerebrovascular event patients with persistent or paroxysmal atrial fibrillation, anticoagulation with adjusted‐dose warfarin (target international normalized ratio [INR] of 2.5; range, 2.0‐3.0) should be administered.47 The ASA recommends initiating oral anticoagulation within 2 weeks of an ischemic stroke or TIA but indicates that further delays may be appropriate for patients with large infarcts or uncontrolled hypertension.2 For patients unable to take oral anticoagulants, aspirin 325 mg/day should be given instead. Among patients who suffered an ischemic stroke or TIA because of an acute myocardial infarction in whom left ventricular mural thrombus is identified by echocardiography or another form of cardiac imaging, oral anticoagulation should be considered, aiming for an INR of 2.0‐3.0 for at least 3 months and up to 1 year.2 Patients receiving oral anticoagulation who also have ischemic coronary artery disease should be prescribed aspirin as well, in doses up to 162 mg/day.2
Noncardioembolic Stroke Mechanism
For ischemic stroke or TIA patients who have no high‐risk source of cardiogenic embolism, antiplatelet agents rather than oral anticoagulation are generally recommended to reduce the risk of recurrent stroke and other cardiovascular events.4850 Acceptable options for initial therapy include:
-
Aspirin (50 to 325 mg/day)48;
-
Combination of aspirin (50 mg) and extended‐release dipyridamole (400 mg) daily49, 51;
-
Clopidogrel (75 mg) daily.50
The combination of aspirin and extended‐release dipyridamole is suggested instead of aspirin alone, and clopidogrel may be considered instead of aspirin alone.49, 51 However, currently there is not enough data to make evidence‐based recommendations for choosing between antiplatelet drugs beyond aspirin.2 Furthermore, there is no evidence that increasing the dose of aspirin for patients who have had an ischemic stroke while taking aspirin provides additional benefit.2 The selection of an antiplatelet agent must be individualized, giving due consideration to a patient's presumed stroke mechanism, risk factor profile, and tolerance.
Other antiplatelet guidelines for noncardioembolic stroke/TIA patients include that:
Education for Behavior Modification
It is crucial to discharge patients with the tools they need to make important lifestyle changes. Patients can significantly reduce their stroke risk by making changes in their everyday patterns of behavior. As much education as possible about smoking cessation, exercise, diet, and the warning signs of stroke should be provided often as possible during hospitalization for a stroke and need not be left to nurses. Stroke education is extremely important so patients understand the need to call for emergency medical services immediately if they even suspect they are having stroke symptoms because of the very narrow window of opportunity for treatment of an acute stroke.54 All patients should be encouraged to make lifestyle adjustments such as ceasing smoking, reducing alcohol intake, and controlling weight. Smoking cessation appears to be effective in preventing secondary stroke (33% reduction in relative risk),44 and initiating smoking cessation counseling during hospitalization for stroke may result in a high rate of adherence to smoking cessation, at least in the short term.55 Table 3 displays current national guideline recommendations on lifestyle modification approaches.2
| Risk Factor | Recommendation |
|---|---|
| |
| Smoking | Smoking cessation |
| Avoid environmental smoke | |
| Counseling, nicotine products, and oral smoking cessation medications | |
| Alcohol | Eliminate or reduce alcohol consumption |
| Light to moderate levels2 drinks/day for men, 1 drink/day for nonpregnant women may be considered | |
| Obesity | Weight reduction goal: BMI 18.5‐24.9 kg/m2 and waist circumference < 35 inches for women, < 40 inches for men |
| Encourage weight management through balance of caloric intake, physical activity, behavioral counseling | |
| Physical Activity | At least 30 minutes of moderate‐intensity physical exercise most days of the week |
| Supervised therapeutic exercise regimen for those with residual disability | |
EvidencePractice Gap
There are now many secondary stroke prevention modalities, and there is a copious amount of data validating the efficacy of quite a few of them.2 Yet there is a large gap in implementing evidence‐based secondary prevention strategies.35 TIA and ischemic stroke patients are often discharged from the hospital without being prescribed any preventive medications, despite the data supporting the use of antiplatelet agents, anticoagulants, and antihypertensives for prevention of secondary stroke.4 In addition, several behavioral interventions could help patients to avoid stroke recurrence,2 but quite often stroke patients are not educated about them during the acute care period.4 Poor discharge treatment utilization limits the effectiveness of proven therapies, resulting in lost opportunities to reduce the burden of secondary stroke.
The reasons for these care gaps are multifactorial and can be traced to patient and provider issues as well as to health care delivery processes. Our understanding of the reasons for this gap is improving. Generally speaking, preventive services are used less frequently than those services or treatment modalities that provide immediate relief or economic benefit. The benefit of most preventive services is more readily seen at a population level than at a individual level and accrues slowly over time. It becomes more difficult to stress prevention in a health care system driven by technology‐based acute care.3
Current clinical management of acute stroke patients has stroke specialists and hospital physicians focusing on the acute management and diagnostic workup during hospitalization. Initiation of long‐term treatment is often deferred to after discharge, when the patient resumes long‐term primary care follow‐up.54 This deferred approach may result in therapy not being initiated or being initiated less efficiently and at a time (weeks or months after the initial presentation) when the stroke event and underlying atherosclerotic disease may no longer be the focus of either the patient or the primary care physician.54
Initiating medications during the acute stroke hospitalization phase sends the patient the message that these therapies are important for preventing recurrence and are an essential part of their treatment.54 More important, hospital initiation of secondary prevention therapies has been shown to be a strong predictor of these therapies continuing to be used after discharge56 and is associated with better clinical outcomes.5759 Table 4 shows some of the resources available to assist hospitalists in overcoming the evidencepractice gap in stroke treatment.
| Tool | Description |
|---|---|
| |
| AHA Get with the GuidelinesStroke ( |
Focuses on care team protocols to facilitate appropriate in‐hospital and discharge stroke treatment utilization |
| Identifies champions to lead, develop, and mobilize teams to optimally implement evidence‐based stroke treatment in acute care hospitals | |
| Utilizes standardized admission orders, patient educational materials, data monitoring | |
| Provides resources to help hospitals obtain JCAHO certification | |
| UCLA Stroke PROTECT (Preventing Recurrence of Thromboembolic Events through Coordinated Treatment) program ( |
Integrates 8 proven secondary stroke prevention measures into standard stroke care provided during hospitalization |
| Applies quality improvement measures through preprinted admission orders, care maps, discharge protocols, educational materials, patient self‐assessment logs, and data monitoring tools | |
| JCAHO Disease Specific Certification for acute stroke care ( |
Designates eligible hospitals as primary stroke centers |
| Promotes compliance with consensus‐based national standards | |
| Encourages effective use of established clinical practice guidelines to manage and optimize stroke care | |
| Fosters an organized approach to performance measurement and improvement activities | |
CONCLUSIONS
The acute stroke hospitalization setting provides the ideal opportunity for hospitalists to not only institute evidence‐based prevention therapies for recurrent stroke but also to have the undivided attention of patients and their families. Furthermore, it may be risky to assume that relevant therapy when deferred will be initiated in a timely fashion, if at all, after hospital discharge. As part of an effective continuum of care, hospitalists have an important role not just in the management of acute ischemic stroke, but also in long‐term reduction of vascular risk.
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- ,,, et al.Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co‐sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline.Stroke.2006;37:577–617.
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- ,,, et al.Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry.Stroke.2005;36:1232–1240.
- ,,.,.Lipid Assessment and treatment patterns in hospitalized TIA and ischemic stroke patients.J Hosp Med.2006;1:214–220.
- ,,, et al.Heart disease and stroke statistics—2006 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation.2006;113(6):e85–e151.
- .Long‐term outcome after ischaemic stroke/transient ischaemic attack.Cerebrovasc Dis.2003;16(Suppl 1):14–19.
- ,,,,.Ten‐year survival after first‐ever stroke in the perth community stroke study.Stroke.2003;34:1842–1846.
- NINDS rt‐PA Stroke Group.Tissue plasminogen activator for acute ischemic stroke.N Engl J Med.1995;333:1581–1587.
- ,,,,,.Assessing patterns of t‐PA use in acute stroke.Stroke.2002;33:354.
- Growth of hospital medicine nationwide. Available at: http://www.hospitalmedicine.org/Content/NavigationMenu/Media/GrowthofHospitalMedicineNationwide/Growth_of_ Hospital_M.htm. Accessed April 12,2006.
- American Academy of Neurology. Available at: http://www.aan.com/students/medical/faq.cfm. Accessed June 25,2006.
- .The neurologist's role in stroke management.Stroke.1996;27:1935–1936.
- .Prevention and management of medical complications of the hospitalized elderly stroke patient.Clin Geriatr Med.1991;7:475–482.
- ,,, et al.The Stroke Prevention Policy Model: linking evidence and clinical decisions.Ann Intern Med.1997;127:704–711.
- ,,.Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services.BMJ.2004;328:326.
- ,,, et al.Incidence and short‐term prognosis of transient ischemic attack in a population‐based study.Stroke.2005;36:720–723.
- ,,.Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services.BMJ.2004;328:326.
- ,,,.Short‐term prognosis after emergency department diagnosis of TIA.JAMA.2000;284:2901–2906.
- ,,,,.Ten‐year risk of first recurrent stroke and disability after first‐ever stroke in the Perth Community Stroke Study.Stroke.2004;35:731–735.
- .New strategies for prevention of ischemic stroke: the LIFE study.Curr Neurol Neurosci Rep.2003;3(1):46–51.
- ,,, et al.[Manifestations of atherosclerosis in various vascular regions. Similarities and differences regarding epidemiology, etiology and prognosis].Med Klin.2002;97(4):221–228.
- ,,,,,.Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences.Ann Intern Med.2001;134(3):224–238.
- .Prevention of strokes and recurrent strokes.J Neurol Neurosurg Psychiatry.1998;64:716.
- ,.Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital‐based geriatrics practice.J Am Geriatr Soc.1999;47:1255–1256.
- ,,.Risk factors and their management for stroke prevention: outlook for 1999 and beyond.Neurology.1999;53(7 Suppl 4):S15–S24.
- ,,,,.Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. Sep2004;126(3 Suppl):483S–512S.
- Randomised trial of a perindopril‐based blood‐pressure‐lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack.Lancet.2001;358:1033–1041.
- ,,.Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review.Stroke.2003;34:2741–2748.
- Post‐stroke antihypertensive treatment study. A preliminary result.PATS Collaborating Group.Chin Med J (Engl).1995;108:710–717.
- ,,.Should beta blockers remain first choice in the treatment of primary hypertension? A meta‐analysis.Lancet.2005;366:1545–1553.
- ,,, et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Circulation.2004;110(2):227–239.
- Heart Protection Study Collaborative Group.Effects of cholesterol‐lowering with Simvastatin on stroke and other major vascular events in 20, 536 people with cerebrovascular disease or other high‐risk conditions.Lancet.2004;363:757–767.
- , et al.The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. Presented at the 15th European Stroke Conference, Brussels, Belgium, May 16‐19,2006.
- Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38: UK Prospective Diabetes Study Group.BMJ.1998;317:703–713.
- ,,,,, for theHeart Protection Study Collaborative Group.MRC/BHF Heart Protection Study of cholesterol‐lowering with simvastatin in 5963 people with diabetes: a randomised placebo‐controlled trial.Lancet.2003;361:2005–2016.
- ,,,.The effect of angiotensin‐converting‐enzyme inhibition on diabetic nephropathy: the Collaborative Study Group.N Engl J Med.1993;329:1456–1462.
- ,,, for theCollaborative Study Group.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med.2001;345:861–869.
- ,,., et al.Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non‐insulin‐dependent diabetes mellitus: a randomized prospective 6‐year study.Diabetes Res Clin Pract.1995;28:103–117.
- Beneficial effect of carotid endarterectomy in symptomatic patients with high‐grade carotid stenosis.North American Symptomatic Carotid Endarterectomy Trial Collaborators.N Engl J Med.1991;325:445–453.
- ,,, et al.Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis.North American Symptomatic Carotid Endarterectomy Trial Collaborators.N Engl J Med.1998;339:1415–1425.
- Endarterectomy for asymptomatic carotid artery stenosis.Executive Committee for the Asymptomatic Carotid Atherosclerosis Study.JAMA.1995;273:1421–1428.
- ,,, et al.Protected carotid‐artery stenting versus endarterectomy in high‐risk patients.N Engl J Med.2004;351:1493–1501.
- ,,.New evidence for stroke prevention: scientific review.JAMA.2002;288:1388–1395.
- ,,,,.Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery.Lancet.2004;363:915–924.
- .Carotid artery surgery vs. stent: a cardiovascular perspective.Catheter Cardiovasc Interv.2004;63:377–384.
- ,,, et al.Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis.Chest.2004;126:1938–1945.
- Collaborative meta‐analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.BMJ.2002;324:71–86.
- ,,,,,.European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.J Neurol Sci.1996;143(1‐2):1–13.
- A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).CAPRIE Steering Committee.Lancet.1996;348:1329–1339.
- ,,,,.Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial.Lancet.2006;367:1665–1673.
- ,,, et al.Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high‐risk patients (MATCH): randomised, double‐blind, placebo‐controlled trial.Lancet.2004;364:331–337.
- ,,, et al.Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. Apr 202006;354(16):1706–1717.
- ,,, et al.PROTECT: A Coordinated Stroke Treatment Program to Prevent Recurrent Thromboembolic Events.Neurology. Vol63;2004:1217–1222.
- ,,, et al.In‐hospital initiation of secondary stroke prevention therapies yields high rates of adherence at follow up.Stroke.2004;35:2879–2883.
- ,,, et al.In‐hospital initiation of lipid‐lowering therapy after coronary intervention as a predictor of long‐term utilization: a propensity analysis.Arch Intern Med.2003;163:2576–2582.
- ,,, et al.Early effects of statins in patients with coronary artery disease and high C‐reactive protein.Am J Cardiol.2004;94:1107–1112.
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Prevention has the greatest potential to reduce the societal burden from stroke.1 Several therapies that specifically target the underlying atherosclerotic disease process have been shown in clinical trials to markedly lower the risk of recurrent vascular events including stroke.2 However, there is great variability in how clinical trial data are implemented in clinical practice for ischemic stroke prevention.35 This has led to a knowledge‐implementation‐practice gap, possibly because of the limited awareness of the scientific evidence supporting various treatments, as well as the lack of a systematic approach to hospital stroke care.3 Our review discusses the evidence for reducing vascular risk after ischemic stroke and successful models of systematic interventions initiated during stroke hospitalization, with the goal of narrowing the stroke hospitalization evidencepractice gap.
Societal Burden
Stroke is the third‐leading cause of death in the United States and the leading cause of serious long‐term disability.6 Approximately 700,000 Americans have a new stroke or recurrent strokes every year, whereas nearly 5 million live with the consequences of stroke; nearly all stroke survivors (90%) have some residual functional deficit, and approximately 40% experience moderate to severe impairment.6 Stroke mortality is substantial, with a 30‐day case fatality rate after first stroke (of any cause) of about 25%.7, 8 Indeed, four‐fifths of patients do not survive for 10 years after stroke, and approximately one‐third of all case fatalities occur in the first year after a stroke.8 The estimated economic impact in 2006, US$57.9 billion, further underscores the substantial mortality and morbidity of stroke.6 Given the limited options for acute stroke therapies,9 stroke prevention remains an important therapeutic goal, especially because fewer than 5% of acute stroke patients in the United States currently receive the only Food and Drug Administrationapproved treatmentintravenous tissue plasminogen activator.10 It is obvious that additional strategies are urgently needed to reduce the devastating consequences of stroke.
Why Involve the Hospitalist?
The Hospitalist system in the United States is rapidly growing.11 Tthe Society of Hospital Medicine projects that by 2010 there will be approximately 30,000 hospitalists in the United States.11 A member census conducted by the American Academy of Neurology in 2000 found 13,500 practicing neurologists, most of whom are concentrated in urban and metropolitan areas.12 As such, with more than 700,000 strokes occurring each year,6 most stroke patients in the United States will not be seen or evaluated by a neurologist. Indeed, one study indicated that only 11.3% of stroke patients are attended exclusively by a neurologist.13 Furthermore, it is not uncommon for stroke patients to have numerous other medical issues that require attention and multidisciplinary care coordination during the hospital stay, an area where hospitalists excel. Conceivably, the ability to promptly identify and treat these non‐neurological comorbidities, which account for at least 30% of the deaths from acute ischemic stroke,14 could go a long way toward improving stroke outcomes.
Hospitalists are in the forefront of developing strategies for improving the quality of acute care and patient satisfaction, reducing medical errors, and focusing on efficient resource utilization. Translating evidence‐based strategies for acute stroke care into actual practice is a mechanism for improving the quality of care, ensuring that basic care does not deviate from provider to provider or from day to day (weekdays compared to weekend days/holidays) while at the same time allowing for the individualization of care appropriate to a patient's unique needs.15 After the acute treatment of stroke or TIA, additional measures must be initiated as soon as it is safe to do so in order to begin the process of limiting stroke progression and preventing recurrence. Secondary prevention measures require a coordinated transition in order to ensure continuation of care and follow‐up as needed. After a thorough risk assessment is complete, hospitalists will need to consider a 3‐pronged approach to secondary prevention that follows the national guidelines described above: pharmacotherapy, behavior modification, and, in some cases, surgical intervention.
Secondary Stroke
Secondary or recurrent strokes are strokes that occur after a first stroke or TIA,2 and the single biggest risk factor for having a stroke is already having had one.2 Because hospitalists generally see patients after ischemic cerebrovascular events have already happened, their opportunities to intervene are mostly geared toward reducing the risk of secondary stroke (beyond enhancing the prevention of complications from the index event). Recent community‐based data indicate that the short‐term risk of secondary stroke is high.16, 17 After a minor stroke or TIA, the risk of recurrent stroke or TIA increases over time8%‐12% within 7 days, 12%‐15% within 30 days, and 17%‐19% within 90 days.18 In the largest study of short‐term risk following TIA,19 there was an 11% risk of stroke (51% of which occurred in the 48 hours after TIA), an 13% risk of TIA, and a 25% risk of any adverse event within 90 days of the TIA.
Overall, the risk of a second cerebrovascular event is highest in the first year after a stroke/TIA (12%), declining to about 5% annually thereafter.7 The effects of secondary stroke are more devastating than those of the primary stroke: the 30‐day fatality rate after a first recurrent stroke is almost double that after the first‐ever stroke (41% versus 22%).20 The pathological factors that lead to TIA and stroke, such as platelet aggregation and subsequent thrombosis or the systolic stroke of blood against stenotic carotid plaques, are one and the same. As such, the short‐ and long‐term risks of recurrent events after both first stroke or first TIA necessitate investigation into a patient's vascular risk and early initiation of appropriate stroke prevention strategies.21
Cross Risk
Because the atherothrombotic disease process is systemic in nature with a variety of manifestations, stroke patients with atherosclerosis frequently have coexistent coronary artery disease and peripheral artery disease,22 and as such, are at risk for vascular events emanating from any of these beds in addition to that of the cervicocephalic arterial tree.23, 24 For instance, in a study of individuals in a long‐term care facility, among the patients with ischemic stroke, 56% had overlapping coronary artery disease, 28% had peripheral artery disease,25 and 38% of the patients had at least 2 manifestations of their atherosclerotic disease. The take‐home message here is that hospitalists also have the opportunity while treating patients hospitalized following stroke to prevent other vascular events by identifying and treating stroke patients who have systemic atherosclerosis.
Risk Factors
The first step in any approach to stroke prevention is the identification of predisposing risk factors. Several of the known biological and lifestyle risk factors associated with cerebrovascular disease were identified decades ago from large longitudinal studies.2 Certain stroke risk factors are nonmodifiable and therefore cannot be the target of intervention. 26 Treatment of the various stroke risk factors could have a substantial impact on reducing the burden of stroke. Table 1 shows the number needed to treat to prevent one stroke per year by modification of the individual stroke risk factor.
| Treatment | Relative risk reduction | Number needed to treat (1 stroke/year) |
|---|---|---|
| ||
| Antihypertensives | 28% | 51 |
| Statins | 25% | 57 |
| Aspirin | 28% | 77 |
| Smoking cessation | 33% | 43 |
| Carotid endarterectomy | 44% | 26 |
Guidelines for Secondary Stroke Prevention
Several organizations have published guidelines for the prevention of secondary stroke based on clinical evidence and expert consensus. Key guidelines include those published by the American Stroke Association (ASA),2 American College of Chest Physicians (ACCP),27 and the National Stroke Association. Although these guidelines are broadaddressing many components of stroke prevention and careeach contains recommendations specifically applicable to secondary prevention in most stroke patients who the hospitalist will encounter. Some provide hospital‐based guidelines that focus on care protocols and systems processes (ie, ASA Stroke Systems Guidelines), whereas others are therapy‐based guidelines (i.e, ACCP Guidelines on Antithrombotic Therapy for Ischemic Stroke). In the next few sections, we discuss common risk factors for and causes of secondary stroke and the prevailing guideline recommendations for modifying them. Discussion of the management of rare causes of ischemic stroke such as arterial dissection, vasculitis, patent foramen ovale, and so forth is beyond the scope of this article.
Hypertension, Dyslipidemia, and Diabetes
Table 2 shows the current national guideline recommendations for the management of premier vascular risk factorshypertension, dyslipidemia, and diabetesin ischemic stroke and TIA patients.2 Antihypertensive therapy is recommended for the prevention of secondary stroke and other vascular events in patients who have experienced an ischemic stroke or TIA and are beyond the hyperacute period.28, 29 Such treatment should be considered for all ischemic stroke and TIA patients regardless of history of hypertension.28 Although available data support the use of diuretics and the combination of diuretics plus an angiotensin‐converting enzyme inhibitor,28, 30 selection of specific medications should be individualized according to a patient's comorbid conditions.29 It is also important to note that despite the proven benefit of beta blockers in the secondary prevention of recurrent cardiac events, current evidence shows no clear benefit from the use of beta blockers in the prevention of stroke.29, 31
| Risk Factor | Recommendation |
|---|---|
| |
| Hypertension | Antihypertensive beyond hyperacute stroke period60 |
| Data support diuretic or diuretic + ACEI,2830 but individualize based on patient characteristics | |
| Antihypertensive in all patients regardless of history of hypertension28 | |
| Aim for average reduction of 10/5 mm HG or blood pressure < 120/80 mm Hg28 | |
| Encourage reduced intake of dietary salt | |
| Dyslipidemia | Statin for LDL‐C goal < 100 mg/dL in those with CAD or symptomatic atherosclerosis33, 34 |
| Target LDL‐C < 70 mg/dL for very high‐risk persons61 | |
| Statin for stroke or TIA because of atherosclerosis regardless of LDL‐C level33, 34 | |
| Niacin or gemfibrozil for patients with low HDL‐C62, 63 | |
| Diabetes | ACEIs and ARBs should be first‐choice blood pressure drugs37, 38a |
| Glucose control to near normoglycemic levels39 | |
| Target glycosylated hemoglobin 7%64 | |
For ischemic cerebrovascular disease patients with dyslipidemia or symptomatic atherosclerosis, cholesterol management should be according to the current Adult Treatment Panel (ATP) guidelines.32 Statins should be the first‐line treatment.33, 34 Ischemic stroke or TIA patients whose underlying stroke mechanism is presumed to be atherosclerosis should be considered for statin therapy even if they have normal cholesterol levels and no evidence of atherosclerosis.33, 34 The recent Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study was the first study to specifically investigate the effect of statins in patients with a prior stroke but with normal cholesterol levels and no evidence of coronary heart disease. It found that treatment with atorvastatin 80 mg/day (vs. placebo) was associated with a 16% reduction in relative risk of recurrent stroke.34
The care of an ischemic stroke or TIA patient who has diabetes warrants more rigorous control of blood pressure and lipids.35, 36 Such patients usually require more than one antihypertensive drug. ACEIs and angiotensin receptor blockers (ARBs) are more effective in reducing the progression of renal disease and are the recommended first‐choice medications for these patients.37, 38 The target for glucose control should be reaching near‐normoglycemic levels.39
Large‐Artery Atherosclerosis
In selected at‐risk stroke patients, surgical techniques (eg, carotid endarterectomy [CEA], carotid angioplasty and/or stenting [CAS]) may reduce the rate of recurrent stroke.4044 For patients who have had ischemic cerebrovascular events in the preceding 6 months and who have ipsilateral severe (70%‐99%) cervical carotid artery stenosis, CEA done by a surgeon is recommended; it has a perioperative morbidity and mortality of less than 6%.40 For those with ipsilateral moderate (50%‐69%) cervical carotid stenosis, CEA should be considered, and whether to operate should be decided on the basis of the patient's age, sex, comorbidities, and severity of initial symptoms.41 Analyses of endarterectomy trials indicated that the benefit from CEA is greatest if performed within 2 weeks of a patient's last ischemic event, the advantage it confers rapidly falling with increasing delay.45 From the hospitalist's standpoint, it is of prime importance to ensure that patients admitted to the hospital with a TIA or ischemic stroke are not discharged before it has been established whether have severe carotid stenosis that requires a revascularization procedure. If carotid stenosis is less than 50%, CEA is not recommended.41
A newer, less invasive form of carotid artery revascularization is CAS,46 which is performed by operators with established periprocedural morbidity and mortality rates of 4%‐6% and may be considered in those with:
-
Symptomatic severe stenosis (>70%) that is difficult to access surgically.2
-
Medical issues that greatly increase the risks of surgery, such as clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal nerve palsy, radiation‐induced stenosis or restenosis after carotid endarterectomy, and more than 80 years old.43
Angioplasty and/or stenting may also be considered when patients with symptomatic extracranial vertebral stenosis are having symptoms despite optimal medical risk factor treatments.2 Among those with hemodynamically significant stenosis of the major intracranial vasculature (basilar, middle cerebrals, distal carotids, and vertebrals) experiencing symptoms despite optimal medical risk factor treatments, angioplasty and/or stenting is considered experimental.2
The degree of arterial stenosis can be assessed by ultrasound, magnetic resonance angiogram (MRA), computed tomography angiogram (CTA), and conventional catheter angiogram, the last of which remains the gold standard. A carotid ultrasound performed at a certified vascular laboratory or by an experienced radiology technologist that shows less than 50% stenosis need not be followed up with another neuroimaging test. Generally, MRA tends to overestimate the degree of arterial stenosis but is a useful screening tool. In the event that an MRA reveals more than 50% stenosis, another diagnostic modality such as a carotid duplex, CTA, or conventional catheter angiogram should be performed to confirm this finding.
Antithrombotic Treatment
Cardioembolic Stroke Mechanism
Although it can sometimes be difficult to determine the precise mechanism underlying a patient's stroke or TIA, those who have a high‐risk source of cardiogenic embolism should generally be treated with anticoagulant medications to prevent recurrence.2 Among ischemic cerebrovascular event patients with persistent or paroxysmal atrial fibrillation, anticoagulation with adjusted‐dose warfarin (target international normalized ratio [INR] of 2.5; range, 2.0‐3.0) should be administered.47 The ASA recommends initiating oral anticoagulation within 2 weeks of an ischemic stroke or TIA but indicates that further delays may be appropriate for patients with large infarcts or uncontrolled hypertension.2 For patients unable to take oral anticoagulants, aspirin 325 mg/day should be given instead. Among patients who suffered an ischemic stroke or TIA because of an acute myocardial infarction in whom left ventricular mural thrombus is identified by echocardiography or another form of cardiac imaging, oral anticoagulation should be considered, aiming for an INR of 2.0‐3.0 for at least 3 months and up to 1 year.2 Patients receiving oral anticoagulation who also have ischemic coronary artery disease should be prescribed aspirin as well, in doses up to 162 mg/day.2
Noncardioembolic Stroke Mechanism
For ischemic stroke or TIA patients who have no high‐risk source of cardiogenic embolism, antiplatelet agents rather than oral anticoagulation are generally recommended to reduce the risk of recurrent stroke and other cardiovascular events.4850 Acceptable options for initial therapy include:
-
Aspirin (50 to 325 mg/day)48;
-
Combination of aspirin (50 mg) and extended‐release dipyridamole (400 mg) daily49, 51;
-
Clopidogrel (75 mg) daily.50
The combination of aspirin and extended‐release dipyridamole is suggested instead of aspirin alone, and clopidogrel may be considered instead of aspirin alone.49, 51 However, currently there is not enough data to make evidence‐based recommendations for choosing between antiplatelet drugs beyond aspirin.2 Furthermore, there is no evidence that increasing the dose of aspirin for patients who have had an ischemic stroke while taking aspirin provides additional benefit.2 The selection of an antiplatelet agent must be individualized, giving due consideration to a patient's presumed stroke mechanism, risk factor profile, and tolerance.
Other antiplatelet guidelines for noncardioembolic stroke/TIA patients include that:
Education for Behavior Modification
It is crucial to discharge patients with the tools they need to make important lifestyle changes. Patients can significantly reduce their stroke risk by making changes in their everyday patterns of behavior. As much education as possible about smoking cessation, exercise, diet, and the warning signs of stroke should be provided often as possible during hospitalization for a stroke and need not be left to nurses. Stroke education is extremely important so patients understand the need to call for emergency medical services immediately if they even suspect they are having stroke symptoms because of the very narrow window of opportunity for treatment of an acute stroke.54 All patients should be encouraged to make lifestyle adjustments such as ceasing smoking, reducing alcohol intake, and controlling weight. Smoking cessation appears to be effective in preventing secondary stroke (33% reduction in relative risk),44 and initiating smoking cessation counseling during hospitalization for stroke may result in a high rate of adherence to smoking cessation, at least in the short term.55 Table 3 displays current national guideline recommendations on lifestyle modification approaches.2
| Risk Factor | Recommendation |
|---|---|
| |
| Smoking | Smoking cessation |
| Avoid environmental smoke | |
| Counseling, nicotine products, and oral smoking cessation medications | |
| Alcohol | Eliminate or reduce alcohol consumption |
| Light to moderate levels2 drinks/day for men, 1 drink/day for nonpregnant women may be considered | |
| Obesity | Weight reduction goal: BMI 18.5‐24.9 kg/m2 and waist circumference < 35 inches for women, < 40 inches for men |
| Encourage weight management through balance of caloric intake, physical activity, behavioral counseling | |
| Physical Activity | At least 30 minutes of moderate‐intensity physical exercise most days of the week |
| Supervised therapeutic exercise regimen for those with residual disability | |
EvidencePractice Gap
There are now many secondary stroke prevention modalities, and there is a copious amount of data validating the efficacy of quite a few of them.2 Yet there is a large gap in implementing evidence‐based secondary prevention strategies.35 TIA and ischemic stroke patients are often discharged from the hospital without being prescribed any preventive medications, despite the data supporting the use of antiplatelet agents, anticoagulants, and antihypertensives for prevention of secondary stroke.4 In addition, several behavioral interventions could help patients to avoid stroke recurrence,2 but quite often stroke patients are not educated about them during the acute care period.4 Poor discharge treatment utilization limits the effectiveness of proven therapies, resulting in lost opportunities to reduce the burden of secondary stroke.
The reasons for these care gaps are multifactorial and can be traced to patient and provider issues as well as to health care delivery processes. Our understanding of the reasons for this gap is improving. Generally speaking, preventive services are used less frequently than those services or treatment modalities that provide immediate relief or economic benefit. The benefit of most preventive services is more readily seen at a population level than at a individual level and accrues slowly over time. It becomes more difficult to stress prevention in a health care system driven by technology‐based acute care.3
Current clinical management of acute stroke patients has stroke specialists and hospital physicians focusing on the acute management and diagnostic workup during hospitalization. Initiation of long‐term treatment is often deferred to after discharge, when the patient resumes long‐term primary care follow‐up.54 This deferred approach may result in therapy not being initiated or being initiated less efficiently and at a time (weeks or months after the initial presentation) when the stroke event and underlying atherosclerotic disease may no longer be the focus of either the patient or the primary care physician.54
Initiating medications during the acute stroke hospitalization phase sends the patient the message that these therapies are important for preventing recurrence and are an essential part of their treatment.54 More important, hospital initiation of secondary prevention therapies has been shown to be a strong predictor of these therapies continuing to be used after discharge56 and is associated with better clinical outcomes.5759 Table 4 shows some of the resources available to assist hospitalists in overcoming the evidencepractice gap in stroke treatment.
| Tool | Description |
|---|---|
| |
| AHA Get with the GuidelinesStroke ( |
Focuses on care team protocols to facilitate appropriate in‐hospital and discharge stroke treatment utilization |
| Identifies champions to lead, develop, and mobilize teams to optimally implement evidence‐based stroke treatment in acute care hospitals | |
| Utilizes standardized admission orders, patient educational materials, data monitoring | |
| Provides resources to help hospitals obtain JCAHO certification | |
| UCLA Stroke PROTECT (Preventing Recurrence of Thromboembolic Events through Coordinated Treatment) program ( |
Integrates 8 proven secondary stroke prevention measures into standard stroke care provided during hospitalization |
| Applies quality improvement measures through preprinted admission orders, care maps, discharge protocols, educational materials, patient self‐assessment logs, and data monitoring tools | |
| JCAHO Disease Specific Certification for acute stroke care ( |
Designates eligible hospitals as primary stroke centers |
| Promotes compliance with consensus‐based national standards | |
| Encourages effective use of established clinical practice guidelines to manage and optimize stroke care | |
| Fosters an organized approach to performance measurement and improvement activities | |
CONCLUSIONS
The acute stroke hospitalization setting provides the ideal opportunity for hospitalists to not only institute evidence‐based prevention therapies for recurrent stroke but also to have the undivided attention of patients and their families. Furthermore, it may be risky to assume that relevant therapy when deferred will be initiated in a timely fashion, if at all, after hospital discharge. As part of an effective continuum of care, hospitalists have an important role not just in the management of acute ischemic stroke, but also in long‐term reduction of vascular risk.
Prevention has the greatest potential to reduce the societal burden from stroke.1 Several therapies that specifically target the underlying atherosclerotic disease process have been shown in clinical trials to markedly lower the risk of recurrent vascular events including stroke.2 However, there is great variability in how clinical trial data are implemented in clinical practice for ischemic stroke prevention.35 This has led to a knowledge‐implementation‐practice gap, possibly because of the limited awareness of the scientific evidence supporting various treatments, as well as the lack of a systematic approach to hospital stroke care.3 Our review discusses the evidence for reducing vascular risk after ischemic stroke and successful models of systematic interventions initiated during stroke hospitalization, with the goal of narrowing the stroke hospitalization evidencepractice gap.
Societal Burden
Stroke is the third‐leading cause of death in the United States and the leading cause of serious long‐term disability.6 Approximately 700,000 Americans have a new stroke or recurrent strokes every year, whereas nearly 5 million live with the consequences of stroke; nearly all stroke survivors (90%) have some residual functional deficit, and approximately 40% experience moderate to severe impairment.6 Stroke mortality is substantial, with a 30‐day case fatality rate after first stroke (of any cause) of about 25%.7, 8 Indeed, four‐fifths of patients do not survive for 10 years after stroke, and approximately one‐third of all case fatalities occur in the first year after a stroke.8 The estimated economic impact in 2006, US$57.9 billion, further underscores the substantial mortality and morbidity of stroke.6 Given the limited options for acute stroke therapies,9 stroke prevention remains an important therapeutic goal, especially because fewer than 5% of acute stroke patients in the United States currently receive the only Food and Drug Administrationapproved treatmentintravenous tissue plasminogen activator.10 It is obvious that additional strategies are urgently needed to reduce the devastating consequences of stroke.
Why Involve the Hospitalist?
The Hospitalist system in the United States is rapidly growing.11 Tthe Society of Hospital Medicine projects that by 2010 there will be approximately 30,000 hospitalists in the United States.11 A member census conducted by the American Academy of Neurology in 2000 found 13,500 practicing neurologists, most of whom are concentrated in urban and metropolitan areas.12 As such, with more than 700,000 strokes occurring each year,6 most stroke patients in the United States will not be seen or evaluated by a neurologist. Indeed, one study indicated that only 11.3% of stroke patients are attended exclusively by a neurologist.13 Furthermore, it is not uncommon for stroke patients to have numerous other medical issues that require attention and multidisciplinary care coordination during the hospital stay, an area where hospitalists excel. Conceivably, the ability to promptly identify and treat these non‐neurological comorbidities, which account for at least 30% of the deaths from acute ischemic stroke,14 could go a long way toward improving stroke outcomes.
Hospitalists are in the forefront of developing strategies for improving the quality of acute care and patient satisfaction, reducing medical errors, and focusing on efficient resource utilization. Translating evidence‐based strategies for acute stroke care into actual practice is a mechanism for improving the quality of care, ensuring that basic care does not deviate from provider to provider or from day to day (weekdays compared to weekend days/holidays) while at the same time allowing for the individualization of care appropriate to a patient's unique needs.15 After the acute treatment of stroke or TIA, additional measures must be initiated as soon as it is safe to do so in order to begin the process of limiting stroke progression and preventing recurrence. Secondary prevention measures require a coordinated transition in order to ensure continuation of care and follow‐up as needed. After a thorough risk assessment is complete, hospitalists will need to consider a 3‐pronged approach to secondary prevention that follows the national guidelines described above: pharmacotherapy, behavior modification, and, in some cases, surgical intervention.
Secondary Stroke
Secondary or recurrent strokes are strokes that occur after a first stroke or TIA,2 and the single biggest risk factor for having a stroke is already having had one.2 Because hospitalists generally see patients after ischemic cerebrovascular events have already happened, their opportunities to intervene are mostly geared toward reducing the risk of secondary stroke (beyond enhancing the prevention of complications from the index event). Recent community‐based data indicate that the short‐term risk of secondary stroke is high.16, 17 After a minor stroke or TIA, the risk of recurrent stroke or TIA increases over time8%‐12% within 7 days, 12%‐15% within 30 days, and 17%‐19% within 90 days.18 In the largest study of short‐term risk following TIA,19 there was an 11% risk of stroke (51% of which occurred in the 48 hours after TIA), an 13% risk of TIA, and a 25% risk of any adverse event within 90 days of the TIA.
Overall, the risk of a second cerebrovascular event is highest in the first year after a stroke/TIA (12%), declining to about 5% annually thereafter.7 The effects of secondary stroke are more devastating than those of the primary stroke: the 30‐day fatality rate after a first recurrent stroke is almost double that after the first‐ever stroke (41% versus 22%).20 The pathological factors that lead to TIA and stroke, such as platelet aggregation and subsequent thrombosis or the systolic stroke of blood against stenotic carotid plaques, are one and the same. As such, the short‐ and long‐term risks of recurrent events after both first stroke or first TIA necessitate investigation into a patient's vascular risk and early initiation of appropriate stroke prevention strategies.21
Cross Risk
Because the atherothrombotic disease process is systemic in nature with a variety of manifestations, stroke patients with atherosclerosis frequently have coexistent coronary artery disease and peripheral artery disease,22 and as such, are at risk for vascular events emanating from any of these beds in addition to that of the cervicocephalic arterial tree.23, 24 For instance, in a study of individuals in a long‐term care facility, among the patients with ischemic stroke, 56% had overlapping coronary artery disease, 28% had peripheral artery disease,25 and 38% of the patients had at least 2 manifestations of their atherosclerotic disease. The take‐home message here is that hospitalists also have the opportunity while treating patients hospitalized following stroke to prevent other vascular events by identifying and treating stroke patients who have systemic atherosclerosis.
Risk Factors
The first step in any approach to stroke prevention is the identification of predisposing risk factors. Several of the known biological and lifestyle risk factors associated with cerebrovascular disease were identified decades ago from large longitudinal studies.2 Certain stroke risk factors are nonmodifiable and therefore cannot be the target of intervention. 26 Treatment of the various stroke risk factors could have a substantial impact on reducing the burden of stroke. Table 1 shows the number needed to treat to prevent one stroke per year by modification of the individual stroke risk factor.
| Treatment | Relative risk reduction | Number needed to treat (1 stroke/year) |
|---|---|---|
| ||
| Antihypertensives | 28% | 51 |
| Statins | 25% | 57 |
| Aspirin | 28% | 77 |
| Smoking cessation | 33% | 43 |
| Carotid endarterectomy | 44% | 26 |
Guidelines for Secondary Stroke Prevention
Several organizations have published guidelines for the prevention of secondary stroke based on clinical evidence and expert consensus. Key guidelines include those published by the American Stroke Association (ASA),2 American College of Chest Physicians (ACCP),27 and the National Stroke Association. Although these guidelines are broadaddressing many components of stroke prevention and careeach contains recommendations specifically applicable to secondary prevention in most stroke patients who the hospitalist will encounter. Some provide hospital‐based guidelines that focus on care protocols and systems processes (ie, ASA Stroke Systems Guidelines), whereas others are therapy‐based guidelines (i.e, ACCP Guidelines on Antithrombotic Therapy for Ischemic Stroke). In the next few sections, we discuss common risk factors for and causes of secondary stroke and the prevailing guideline recommendations for modifying them. Discussion of the management of rare causes of ischemic stroke such as arterial dissection, vasculitis, patent foramen ovale, and so forth is beyond the scope of this article.
Hypertension, Dyslipidemia, and Diabetes
Table 2 shows the current national guideline recommendations for the management of premier vascular risk factorshypertension, dyslipidemia, and diabetesin ischemic stroke and TIA patients.2 Antihypertensive therapy is recommended for the prevention of secondary stroke and other vascular events in patients who have experienced an ischemic stroke or TIA and are beyond the hyperacute period.28, 29 Such treatment should be considered for all ischemic stroke and TIA patients regardless of history of hypertension.28 Although available data support the use of diuretics and the combination of diuretics plus an angiotensin‐converting enzyme inhibitor,28, 30 selection of specific medications should be individualized according to a patient's comorbid conditions.29 It is also important to note that despite the proven benefit of beta blockers in the secondary prevention of recurrent cardiac events, current evidence shows no clear benefit from the use of beta blockers in the prevention of stroke.29, 31
| Risk Factor | Recommendation |
|---|---|
| |
| Hypertension | Antihypertensive beyond hyperacute stroke period60 |
| Data support diuretic or diuretic + ACEI,2830 but individualize based on patient characteristics | |
| Antihypertensive in all patients regardless of history of hypertension28 | |
| Aim for average reduction of 10/5 mm HG or blood pressure < 120/80 mm Hg28 | |
| Encourage reduced intake of dietary salt | |
| Dyslipidemia | Statin for LDL‐C goal < 100 mg/dL in those with CAD or symptomatic atherosclerosis33, 34 |
| Target LDL‐C < 70 mg/dL for very high‐risk persons61 | |
| Statin for stroke or TIA because of atherosclerosis regardless of LDL‐C level33, 34 | |
| Niacin or gemfibrozil for patients with low HDL‐C62, 63 | |
| Diabetes | ACEIs and ARBs should be first‐choice blood pressure drugs37, 38a |
| Glucose control to near normoglycemic levels39 | |
| Target glycosylated hemoglobin 7%64 | |
For ischemic cerebrovascular disease patients with dyslipidemia or symptomatic atherosclerosis, cholesterol management should be according to the current Adult Treatment Panel (ATP) guidelines.32 Statins should be the first‐line treatment.33, 34 Ischemic stroke or TIA patients whose underlying stroke mechanism is presumed to be atherosclerosis should be considered for statin therapy even if they have normal cholesterol levels and no evidence of atherosclerosis.33, 34 The recent Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study was the first study to specifically investigate the effect of statins in patients with a prior stroke but with normal cholesterol levels and no evidence of coronary heart disease. It found that treatment with atorvastatin 80 mg/day (vs. placebo) was associated with a 16% reduction in relative risk of recurrent stroke.34
The care of an ischemic stroke or TIA patient who has diabetes warrants more rigorous control of blood pressure and lipids.35, 36 Such patients usually require more than one antihypertensive drug. ACEIs and angiotensin receptor blockers (ARBs) are more effective in reducing the progression of renal disease and are the recommended first‐choice medications for these patients.37, 38 The target for glucose control should be reaching near‐normoglycemic levels.39
Large‐Artery Atherosclerosis
In selected at‐risk stroke patients, surgical techniques (eg, carotid endarterectomy [CEA], carotid angioplasty and/or stenting [CAS]) may reduce the rate of recurrent stroke.4044 For patients who have had ischemic cerebrovascular events in the preceding 6 months and who have ipsilateral severe (70%‐99%) cervical carotid artery stenosis, CEA done by a surgeon is recommended; it has a perioperative morbidity and mortality of less than 6%.40 For those with ipsilateral moderate (50%‐69%) cervical carotid stenosis, CEA should be considered, and whether to operate should be decided on the basis of the patient's age, sex, comorbidities, and severity of initial symptoms.41 Analyses of endarterectomy trials indicated that the benefit from CEA is greatest if performed within 2 weeks of a patient's last ischemic event, the advantage it confers rapidly falling with increasing delay.45 From the hospitalist's standpoint, it is of prime importance to ensure that patients admitted to the hospital with a TIA or ischemic stroke are not discharged before it has been established whether have severe carotid stenosis that requires a revascularization procedure. If carotid stenosis is less than 50%, CEA is not recommended.41
A newer, less invasive form of carotid artery revascularization is CAS,46 which is performed by operators with established periprocedural morbidity and mortality rates of 4%‐6% and may be considered in those with:
-
Symptomatic severe stenosis (>70%) that is difficult to access surgically.2
-
Medical issues that greatly increase the risks of surgery, such as clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal nerve palsy, radiation‐induced stenosis or restenosis after carotid endarterectomy, and more than 80 years old.43
Angioplasty and/or stenting may also be considered when patients with symptomatic extracranial vertebral stenosis are having symptoms despite optimal medical risk factor treatments.2 Among those with hemodynamically significant stenosis of the major intracranial vasculature (basilar, middle cerebrals, distal carotids, and vertebrals) experiencing symptoms despite optimal medical risk factor treatments, angioplasty and/or stenting is considered experimental.2
The degree of arterial stenosis can be assessed by ultrasound, magnetic resonance angiogram (MRA), computed tomography angiogram (CTA), and conventional catheter angiogram, the last of which remains the gold standard. A carotid ultrasound performed at a certified vascular laboratory or by an experienced radiology technologist that shows less than 50% stenosis need not be followed up with another neuroimaging test. Generally, MRA tends to overestimate the degree of arterial stenosis but is a useful screening tool. In the event that an MRA reveals more than 50% stenosis, another diagnostic modality such as a carotid duplex, CTA, or conventional catheter angiogram should be performed to confirm this finding.
Antithrombotic Treatment
Cardioembolic Stroke Mechanism
Although it can sometimes be difficult to determine the precise mechanism underlying a patient's stroke or TIA, those who have a high‐risk source of cardiogenic embolism should generally be treated with anticoagulant medications to prevent recurrence.2 Among ischemic cerebrovascular event patients with persistent or paroxysmal atrial fibrillation, anticoagulation with adjusted‐dose warfarin (target international normalized ratio [INR] of 2.5; range, 2.0‐3.0) should be administered.47 The ASA recommends initiating oral anticoagulation within 2 weeks of an ischemic stroke or TIA but indicates that further delays may be appropriate for patients with large infarcts or uncontrolled hypertension.2 For patients unable to take oral anticoagulants, aspirin 325 mg/day should be given instead. Among patients who suffered an ischemic stroke or TIA because of an acute myocardial infarction in whom left ventricular mural thrombus is identified by echocardiography or another form of cardiac imaging, oral anticoagulation should be considered, aiming for an INR of 2.0‐3.0 for at least 3 months and up to 1 year.2 Patients receiving oral anticoagulation who also have ischemic coronary artery disease should be prescribed aspirin as well, in doses up to 162 mg/day.2
Noncardioembolic Stroke Mechanism
For ischemic stroke or TIA patients who have no high‐risk source of cardiogenic embolism, antiplatelet agents rather than oral anticoagulation are generally recommended to reduce the risk of recurrent stroke and other cardiovascular events.4850 Acceptable options for initial therapy include:
-
Aspirin (50 to 325 mg/day)48;
-
Combination of aspirin (50 mg) and extended‐release dipyridamole (400 mg) daily49, 51;
-
Clopidogrel (75 mg) daily.50
The combination of aspirin and extended‐release dipyridamole is suggested instead of aspirin alone, and clopidogrel may be considered instead of aspirin alone.49, 51 However, currently there is not enough data to make evidence‐based recommendations for choosing between antiplatelet drugs beyond aspirin.2 Furthermore, there is no evidence that increasing the dose of aspirin for patients who have had an ischemic stroke while taking aspirin provides additional benefit.2 The selection of an antiplatelet agent must be individualized, giving due consideration to a patient's presumed stroke mechanism, risk factor profile, and tolerance.
Other antiplatelet guidelines for noncardioembolic stroke/TIA patients include that:
Education for Behavior Modification
It is crucial to discharge patients with the tools they need to make important lifestyle changes. Patients can significantly reduce their stroke risk by making changes in their everyday patterns of behavior. As much education as possible about smoking cessation, exercise, diet, and the warning signs of stroke should be provided often as possible during hospitalization for a stroke and need not be left to nurses. Stroke education is extremely important so patients understand the need to call for emergency medical services immediately if they even suspect they are having stroke symptoms because of the very narrow window of opportunity for treatment of an acute stroke.54 All patients should be encouraged to make lifestyle adjustments such as ceasing smoking, reducing alcohol intake, and controlling weight. Smoking cessation appears to be effective in preventing secondary stroke (33% reduction in relative risk),44 and initiating smoking cessation counseling during hospitalization for stroke may result in a high rate of adherence to smoking cessation, at least in the short term.55 Table 3 displays current national guideline recommendations on lifestyle modification approaches.2
| Risk Factor | Recommendation |
|---|---|
| |
| Smoking | Smoking cessation |
| Avoid environmental smoke | |
| Counseling, nicotine products, and oral smoking cessation medications | |
| Alcohol | Eliminate or reduce alcohol consumption |
| Light to moderate levels2 drinks/day for men, 1 drink/day for nonpregnant women may be considered | |
| Obesity | Weight reduction goal: BMI 18.5‐24.9 kg/m2 and waist circumference < 35 inches for women, < 40 inches for men |
| Encourage weight management through balance of caloric intake, physical activity, behavioral counseling | |
| Physical Activity | At least 30 minutes of moderate‐intensity physical exercise most days of the week |
| Supervised therapeutic exercise regimen for those with residual disability | |
EvidencePractice Gap
There are now many secondary stroke prevention modalities, and there is a copious amount of data validating the efficacy of quite a few of them.2 Yet there is a large gap in implementing evidence‐based secondary prevention strategies.35 TIA and ischemic stroke patients are often discharged from the hospital without being prescribed any preventive medications, despite the data supporting the use of antiplatelet agents, anticoagulants, and antihypertensives for prevention of secondary stroke.4 In addition, several behavioral interventions could help patients to avoid stroke recurrence,2 but quite often stroke patients are not educated about them during the acute care period.4 Poor discharge treatment utilization limits the effectiveness of proven therapies, resulting in lost opportunities to reduce the burden of secondary stroke.
The reasons for these care gaps are multifactorial and can be traced to patient and provider issues as well as to health care delivery processes. Our understanding of the reasons for this gap is improving. Generally speaking, preventive services are used less frequently than those services or treatment modalities that provide immediate relief or economic benefit. The benefit of most preventive services is more readily seen at a population level than at a individual level and accrues slowly over time. It becomes more difficult to stress prevention in a health care system driven by technology‐based acute care.3
Current clinical management of acute stroke patients has stroke specialists and hospital physicians focusing on the acute management and diagnostic workup during hospitalization. Initiation of long‐term treatment is often deferred to after discharge, when the patient resumes long‐term primary care follow‐up.54 This deferred approach may result in therapy not being initiated or being initiated less efficiently and at a time (weeks or months after the initial presentation) when the stroke event and underlying atherosclerotic disease may no longer be the focus of either the patient or the primary care physician.54
Initiating medications during the acute stroke hospitalization phase sends the patient the message that these therapies are important for preventing recurrence and are an essential part of their treatment.54 More important, hospital initiation of secondary prevention therapies has been shown to be a strong predictor of these therapies continuing to be used after discharge56 and is associated with better clinical outcomes.5759 Table 4 shows some of the resources available to assist hospitalists in overcoming the evidencepractice gap in stroke treatment.
| Tool | Description |
|---|---|
| |
| AHA Get with the GuidelinesStroke ( |
Focuses on care team protocols to facilitate appropriate in‐hospital and discharge stroke treatment utilization |
| Identifies champions to lead, develop, and mobilize teams to optimally implement evidence‐based stroke treatment in acute care hospitals | |
| Utilizes standardized admission orders, patient educational materials, data monitoring | |
| Provides resources to help hospitals obtain JCAHO certification | |
| UCLA Stroke PROTECT (Preventing Recurrence of Thromboembolic Events through Coordinated Treatment) program ( |
Integrates 8 proven secondary stroke prevention measures into standard stroke care provided during hospitalization |
| Applies quality improvement measures through preprinted admission orders, care maps, discharge protocols, educational materials, patient self‐assessment logs, and data monitoring tools | |
| JCAHO Disease Specific Certification for acute stroke care ( |
Designates eligible hospitals as primary stroke centers |
| Promotes compliance with consensus‐based national standards | |
| Encourages effective use of established clinical practice guidelines to manage and optimize stroke care | |
| Fosters an organized approach to performance measurement and improvement activities | |
CONCLUSIONS
The acute stroke hospitalization setting provides the ideal opportunity for hospitalists to not only institute evidence‐based prevention therapies for recurrent stroke but also to have the undivided attention of patients and their families. Furthermore, it may be risky to assume that relevant therapy when deferred will be initiated in a timely fashion, if at all, after hospital discharge. As part of an effective continuum of care, hospitalists have an important role not just in the management of acute ischemic stroke, but also in long‐term reduction of vascular risk.
- .Stroke prevention: windows of opportunity and failed expectations? A discussion of modifiable cardiovascular risk factors and a prevention proposal.Neuroepidemiology.1997;16(4):163–173.
- ,,, et al.Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co‐sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline.Stroke.2006;37:577–617.
- ,,.Stroke prevention: narrowing the evidence‐practice gap.Neurology.2000;54:1899–1906.
- ,,, et al.Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry.Stroke.2005;36:1232–1240.
- ,,.,.Lipid Assessment and treatment patterns in hospitalized TIA and ischemic stroke patients.J Hosp Med.2006;1:214–220.
- ,,, et al.Heart disease and stroke statistics—2006 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation.2006;113(6):e85–e151.
- .Long‐term outcome after ischaemic stroke/transient ischaemic attack.Cerebrovasc Dis.2003;16(Suppl 1):14–19.
- ,,,,.Ten‐year survival after first‐ever stroke in the perth community stroke study.Stroke.2003;34:1842–1846.
- NINDS rt‐PA Stroke Group.Tissue plasminogen activator for acute ischemic stroke.N Engl J Med.1995;333:1581–1587.
- ,,,,,.Assessing patterns of t‐PA use in acute stroke.Stroke.2002;33:354.
- Growth of hospital medicine nationwide. Available at: http://www.hospitalmedicine.org/Content/NavigationMenu/Media/GrowthofHospitalMedicineNationwide/Growth_of_ Hospital_M.htm. Accessed April 12,2006.
- American Academy of Neurology. Available at: http://www.aan.com/students/medical/faq.cfm. Accessed June 25,2006.
- .The neurologist's role in stroke management.Stroke.1996;27:1935–1936.
- .Prevention and management of medical complications of the hospitalized elderly stroke patient.Clin Geriatr Med.1991;7:475–482.
- ,,, et al.The Stroke Prevention Policy Model: linking evidence and clinical decisions.Ann Intern Med.1997;127:704–711.
- ,,.Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services.BMJ.2004;328:326.
- ,,, et al.Incidence and short‐term prognosis of transient ischemic attack in a population‐based study.Stroke.2005;36:720–723.
- ,,.Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services.BMJ.2004;328:326.
- ,,,.Short‐term prognosis after emergency department diagnosis of TIA.JAMA.2000;284:2901–2906.
- ,,,,.Ten‐year risk of first recurrent stroke and disability after first‐ever stroke in the Perth Community Stroke Study.Stroke.2004;35:731–735.
- .New strategies for prevention of ischemic stroke: the LIFE study.Curr Neurol Neurosci Rep.2003;3(1):46–51.
- ,,, et al.[Manifestations of atherosclerosis in various vascular regions. Similarities and differences regarding epidemiology, etiology and prognosis].Med Klin.2002;97(4):221–228.
- ,,,,,.Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences.Ann Intern Med.2001;134(3):224–238.
- .Prevention of strokes and recurrent strokes.J Neurol Neurosurg Psychiatry.1998;64:716.
- ,.Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital‐based geriatrics practice.J Am Geriatr Soc.1999;47:1255–1256.
- ,,.Risk factors and their management for stroke prevention: outlook for 1999 and beyond.Neurology.1999;53(7 Suppl 4):S15–S24.
- ,,,,.Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. Sep2004;126(3 Suppl):483S–512S.
- Randomised trial of a perindopril‐based blood‐pressure‐lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack.Lancet.2001;358:1033–1041.
- ,,.Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review.Stroke.2003;34:2741–2748.
- Post‐stroke antihypertensive treatment study. A preliminary result.PATS Collaborating Group.Chin Med J (Engl).1995;108:710–717.
- ,,.Should beta blockers remain first choice in the treatment of primary hypertension? A meta‐analysis.Lancet.2005;366:1545–1553.
- ,,, et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Circulation.2004;110(2):227–239.
- Heart Protection Study Collaborative Group.Effects of cholesterol‐lowering with Simvastatin on stroke and other major vascular events in 20, 536 people with cerebrovascular disease or other high‐risk conditions.Lancet.2004;363:757–767.
- , et al.The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. Presented at the 15th European Stroke Conference, Brussels, Belgium, May 16‐19,2006.
- Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38: UK Prospective Diabetes Study Group.BMJ.1998;317:703–713.
- ,,,,, for theHeart Protection Study Collaborative Group.MRC/BHF Heart Protection Study of cholesterol‐lowering with simvastatin in 5963 people with diabetes: a randomised placebo‐controlled trial.Lancet.2003;361:2005–2016.
- ,,,.The effect of angiotensin‐converting‐enzyme inhibition on diabetic nephropathy: the Collaborative Study Group.N Engl J Med.1993;329:1456–1462.
- ,,, for theCollaborative Study Group.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med.2001;345:861–869.
- ,,., et al.Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non‐insulin‐dependent diabetes mellitus: a randomized prospective 6‐year study.Diabetes Res Clin Pract.1995;28:103–117.
- Beneficial effect of carotid endarterectomy in symptomatic patients with high‐grade carotid stenosis.North American Symptomatic Carotid Endarterectomy Trial Collaborators.N Engl J Med.1991;325:445–453.
- ,,, et al.Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis.North American Symptomatic Carotid Endarterectomy Trial Collaborators.N Engl J Med.1998;339:1415–1425.
- Endarterectomy for asymptomatic carotid artery stenosis.Executive Committee for the Asymptomatic Carotid Atherosclerosis Study.JAMA.1995;273:1421–1428.
- ,,, et al.Protected carotid‐artery stenting versus endarterectomy in high‐risk patients.N Engl J Med.2004;351:1493–1501.
- ,,.New evidence for stroke prevention: scientific review.JAMA.2002;288:1388–1395.
- ,,,,.Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery.Lancet.2004;363:915–924.
- .Carotid artery surgery vs. stent: a cardiovascular perspective.Catheter Cardiovasc Interv.2004;63:377–384.
- ,,, et al.Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis.Chest.2004;126:1938–1945.
- Collaborative meta‐analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.BMJ.2002;324:71–86.
- ,,,,,.European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.J Neurol Sci.1996;143(1‐2):1–13.
- A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).CAPRIE Steering Committee.Lancet.1996;348:1329–1339.
- ,,,,.Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial.Lancet.2006;367:1665–1673.
- ,,, et al.Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high‐risk patients (MATCH): randomised, double‐blind, placebo‐controlled trial.Lancet.2004;364:331–337.
- ,,, et al.Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. Apr 202006;354(16):1706–1717.
- ,,, et al.PROTECT: A Coordinated Stroke Treatment Program to Prevent Recurrent Thromboembolic Events.Neurology. Vol63;2004:1217–1222.
- ,,, et al.In‐hospital initiation of secondary stroke prevention therapies yields high rates of adherence at follow up.Stroke.2004;35:2879–2883.
- ,,, et al.In‐hospital initiation of lipid‐lowering therapy after coronary intervention as a predictor of long‐term utilization: a propensity analysis.Arch Intern Med.2003;163:2576–2582.
- ,,, et al.Early effects of statins in patients with coronary artery disease and high C‐reactive protein.Am J Cardiol.2004;94:1107–1112.
- ,,,.Improved treatment of coronary heart disease by implementation of a Cardiac Hospitalization Atherosclerosis Management Program (CHAMP).Am J Cardiol. Apr 12001;87(7):819–822.
- ,,.Importance of in‐hospital initiation of evidence‐based medical therapies for heart failure‐a review.Am J Cardiol.2004;94:1155–1160.
- ,,,.Blood pressure and stroke: an overview of published reviews.Stroke.2004;35:1024.
- ,,, et al.Intensive versus moderate lipid lowering with statins after acute coronary syndromes.N Engl J Med.2004;350:1495–1504.
- ,,.Niacin therapy in atherosclerosis.Curr Opin Lipidol.2004;15:659–665.
- ,,, et al.Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA‐HIT).Circulation.2001;103:2828–2833.
- ,,.The effect of long‐term intensified insulin treatment on the development of microvascular complications of diabetes mellitus.N Engl J Med.1993;329:304–309.
- .Stroke prevention: windows of opportunity and failed expectations? A discussion of modifiable cardiovascular risk factors and a prevention proposal.Neuroepidemiology.1997;16(4):163–173.
- ,,, et al.Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co‐sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline.Stroke.2006;37:577–617.
- ,,.Stroke prevention: narrowing the evidence‐practice gap.Neurology.2000;54:1899–1906.
- ,,, et al.Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry.Stroke.2005;36:1232–1240.
- ,,.,.Lipid Assessment and treatment patterns in hospitalized TIA and ischemic stroke patients.J Hosp Med.2006;1:214–220.
- ,,, et al.Heart disease and stroke statistics—2006 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation.2006;113(6):e85–e151.
- .Long‐term outcome after ischaemic stroke/transient ischaemic attack.Cerebrovasc Dis.2003;16(Suppl 1):14–19.
- ,,,,.Ten‐year survival after first‐ever stroke in the perth community stroke study.Stroke.2003;34:1842–1846.
- NINDS rt‐PA Stroke Group.Tissue plasminogen activator for acute ischemic stroke.N Engl J Med.1995;333:1581–1587.
- ,,,,,.Assessing patterns of t‐PA use in acute stroke.Stroke.2002;33:354.
- Growth of hospital medicine nationwide. Available at: http://www.hospitalmedicine.org/Content/NavigationMenu/Media/GrowthofHospitalMedicineNationwide/Growth_of_ Hospital_M.htm. Accessed April 12,2006.
- American Academy of Neurology. Available at: http://www.aan.com/students/medical/faq.cfm. Accessed June 25,2006.
- .The neurologist's role in stroke management.Stroke.1996;27:1935–1936.
- .Prevention and management of medical complications of the hospitalized elderly stroke patient.Clin Geriatr Med.1991;7:475–482.
- ,,, et al.The Stroke Prevention Policy Model: linking evidence and clinical decisions.Ann Intern Med.1997;127:704–711.
- ,,.Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services.BMJ.2004;328:326.
- ,,, et al.Incidence and short‐term prognosis of transient ischemic attack in a population‐based study.Stroke.2005;36:720–723.
- ,,.Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services.BMJ.2004;328:326.
- ,,,.Short‐term prognosis after emergency department diagnosis of TIA.JAMA.2000;284:2901–2906.
- ,,,,.Ten‐year risk of first recurrent stroke and disability after first‐ever stroke in the Perth Community Stroke Study.Stroke.2004;35:731–735.
- .New strategies for prevention of ischemic stroke: the LIFE study.Curr Neurol Neurosci Rep.2003;3(1):46–51.
- ,,, et al.[Manifestations of atherosclerosis in various vascular regions. Similarities and differences regarding epidemiology, etiology and prognosis].Med Klin.2002;97(4):221–228.
- ,,,,,.Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences.Ann Intern Med.2001;134(3):224–238.
- .Prevention of strokes and recurrent strokes.J Neurol Neurosurg Psychiatry.1998;64:716.
- ,.Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital‐based geriatrics practice.J Am Geriatr Soc.1999;47:1255–1256.
- ,,.Risk factors and their management for stroke prevention: outlook for 1999 and beyond.Neurology.1999;53(7 Suppl 4):S15–S24.
- ,,,,.Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. Sep2004;126(3 Suppl):483S–512S.
- Randomised trial of a perindopril‐based blood‐pressure‐lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack.Lancet.2001;358:1033–1041.
- ,,.Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review.Stroke.2003;34:2741–2748.
- Post‐stroke antihypertensive treatment study. A preliminary result.PATS Collaborating Group.Chin Med J (Engl).1995;108:710–717.
- ,,.Should beta blockers remain first choice in the treatment of primary hypertension? A meta‐analysis.Lancet.2005;366:1545–1553.
- ,,, et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Circulation.2004;110(2):227–239.
- Heart Protection Study Collaborative Group.Effects of cholesterol‐lowering with Simvastatin on stroke and other major vascular events in 20, 536 people with cerebrovascular disease or other high‐risk conditions.Lancet.2004;363:757–767.
- , et al.The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. Presented at the 15th European Stroke Conference, Brussels, Belgium, May 16‐19,2006.
- Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38: UK Prospective Diabetes Study Group.BMJ.1998;317:703–713.
- ,,,,, for theHeart Protection Study Collaborative Group.MRC/BHF Heart Protection Study of cholesterol‐lowering with simvastatin in 5963 people with diabetes: a randomised placebo‐controlled trial.Lancet.2003;361:2005–2016.
- ,,,.The effect of angiotensin‐converting‐enzyme inhibition on diabetic nephropathy: the Collaborative Study Group.N Engl J Med.1993;329:1456–1462.
- ,,, for theCollaborative Study Group.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med.2001;345:861–869.
- ,,., et al.Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non‐insulin‐dependent diabetes mellitus: a randomized prospective 6‐year study.Diabetes Res Clin Pract.1995;28:103–117.
- Beneficial effect of carotid endarterectomy in symptomatic patients with high‐grade carotid stenosis.North American Symptomatic Carotid Endarterectomy Trial Collaborators.N Engl J Med.1991;325:445–453.
- ,,, et al.Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis.North American Symptomatic Carotid Endarterectomy Trial Collaborators.N Engl J Med.1998;339:1415–1425.
- Endarterectomy for asymptomatic carotid artery stenosis.Executive Committee for the Asymptomatic Carotid Atherosclerosis Study.JAMA.1995;273:1421–1428.
- ,,, et al.Protected carotid‐artery stenting versus endarterectomy in high‐risk patients.N Engl J Med.2004;351:1493–1501.
- ,,.New evidence for stroke prevention: scientific review.JAMA.2002;288:1388–1395.
- ,,,,.Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery.Lancet.2004;363:915–924.
- .Carotid artery surgery vs. stent: a cardiovascular perspective.Catheter Cardiovasc Interv.2004;63:377–384.
- ,,, et al.Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis.Chest.2004;126:1938–1945.
- Collaborative meta‐analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.BMJ.2002;324:71–86.
- ,,,,,.European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.J Neurol Sci.1996;143(1‐2):1–13.
- A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).CAPRIE Steering Committee.Lancet.1996;348:1329–1339.
- ,,,,.Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial.Lancet.2006;367:1665–1673.
- ,,, et al.Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high‐risk patients (MATCH): randomised, double‐blind, placebo‐controlled trial.Lancet.2004;364:331–337.
- ,,, et al.Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. Apr 202006;354(16):1706–1717.
- ,,, et al.PROTECT: A Coordinated Stroke Treatment Program to Prevent Recurrent Thromboembolic Events.Neurology. Vol63;2004:1217–1222.
- ,,, et al.In‐hospital initiation of secondary stroke prevention therapies yields high rates of adherence at follow up.Stroke.2004;35:2879–2883.
- ,,, et al.In‐hospital initiation of lipid‐lowering therapy after coronary intervention as a predictor of long‐term utilization: a propensity analysis.Arch Intern Med.2003;163:2576–2582.
- ,,, et al.Early effects of statins in patients with coronary artery disease and high C‐reactive protein.Am J Cardiol.2004;94:1107–1112.
- ,,,.Improved treatment of coronary heart disease by implementation of a Cardiac Hospitalization Atherosclerosis Management Program (CHAMP).Am J Cardiol. Apr 12001;87(7):819–822.
- ,,.Importance of in‐hospital initiation of evidence‐based medical therapies for heart failure‐a review.Am J Cardiol.2004;94:1155–1160.
- ,,,.Blood pressure and stroke: an overview of published reviews.Stroke.2004;35:1024.
- ,,, et al.Intensive versus moderate lipid lowering with statins after acute coronary syndromes.N Engl J Med.2004;350:1495–1504.
- ,,.Niacin therapy in atherosclerosis.Curr Opin Lipidol.2004;15:659–665.
- ,,, et al.Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA‐HIT).Circulation.2001;103:2828–2833.
- ,,.The effect of long‐term intensified insulin treatment on the development of microvascular complications of diabetes mellitus.N Engl J Med.1993;329:304–309.
Medication Compliance, the New C. Diff
The Tricky Nature of Medication Compliance
Review by Osterberg L, Blaschke T. Adherence to Medication. N Engl J Med. 2005;353:487-497.
Adherence to (or compliance with) a medication regimen is generally defined as the extent to which patients take medications as prescribed by their healthcare providers. Adherence rates are typically higher among patients with acute conditions, as compared with those with chronic conditions; persistence among patients with chronic conditions is disappointingly low, dropping most drastically after the first six months of therapy. Of all medication-related hospital admissions in the United States, 33% to 69% are because of poor medication adherence, with a resultant cost of approximately $100 billion a year.
Electronic medication-monitoring devices have provided very detailed information about the patterns of medication-taking behavior. Studies using these monitors have shown six general patterns of taking medication among patients treated for chronic illnesses who continue to take their medications. Approximately one-sixth come close to perfect adherence to a regimen; one-sixth take nearly all doses, but with some timing irregularity; one-sixth miss an occasional single day’s dose and have some timing inconsistency; one-sixth take drug holidays three to four times a year, with occasional omissions of doses; one-sixth have a drug holiday monthly or more often, with frequent omissions of doses; and one-sixth take few or no doses while giving the impression of good adherence.
Poor adherence to medication regimens is common, contributing to substantial worsening of disease, death, and increased healthcare costs. Practitioners should always look for poor adherence and can enhance adherence by emphasizing the value of a patient’s regimen, making the regimen simple, and customizing the regimen to the patient’s lifestyle. Asking patients nonjudgmentally about medication-taking behavior is a practical strategy for identifying poor adherence. A collaborative approach to care augments adherence. Patients who have difficulty maintaining adequate adherence need more intensive strategies than do patients who have less difficulty with adherence, a more forgiving medication regimen, or both. Innovative methods of managing chronic diseases have had some success in improving adherence when a regimen has been difficult to follow.
The New Clostridium Difficile—What Does It Mean?
McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxic gene-variant of Clostridium difficile. N Eng J Med. 2005;353;2433-2441.
Clostridium difficile is the only anaerobe that causes nosocomial infections. It colonizes the colon in 3% of the healthy population and about 20% to 40% of hospitalized patients.
This study was done in response to reports of increasing rate and severity of this infection. This study looked at healthcare facilities in Pennsylvania, Maine, Georgia, Oregon, Illinois, and New Jersey and did indeed find a new strain of Clostridium difficile isolate which showed 100% resistance to gatifloxacin and moxifloxacin, compared with no resistance in the historic strain.
Resistance to clindamycin was similar in both the groups, which was measured at 79%. This particular strain secretes 16 to 23 times more toxins A and B in vitro than other strains. And in this study the new strain accounted for 51% of the infections compared with 17% in the historic control isolates. Fluoroquinolones were implicated alone or in combination with other antibiotics in 52% of the cases. Those infected with the new strain were more likely to have higher rates of toxic megacolon, need for colectomy, leukemoid reaction, shock, and death. Like any disease, the interaction between host and pathogen is key to severity, thereby making patients who are chronically ill and elderly more susceptible.
For hospitalists the implications for this study are certainly important. We need to be aware of whether this strain is prevalent in our work environment. Close collaboration with our colleagues from infectious disease services along with monitoring clinical outcomes of patients with Clostridium difficile infection is the need of the hour. Also recommended is investigation of any increases in caseload of this infection. Simple measures such as judicious use of antibiotics, early diagnosis, and appropriate treatment of Clostridium difficile infection and strict isolation of the patients infected or colonized with Clostridium difficile would go a long way in controlling the spread of the new more virulent strain. It must be pointed out that alcohol-based waterless hand-sanitizing agents do not kill the Clostridium difficile spores; washing hands with soap and water is a prudent option after coming in contact with a patient with Clostridium difficile. TH
Nasal MRSA Carriage: A Study of Current Prevalence with Commentary
Creech CB, Kernodle DS, Alsectzer M, et al. Increasing rates of nasal carriage of methicillin-resistant Staphylococcus aureus in healthy children. Pediatr Infect Dis J. 2005;24:617-621.
Review by Laura Ortman, MD
The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections seen in outpatient clinics and emergency rooms appears to be on the rise. In 2001 a study done at Vanderbilt University Medical Center found the prevalence of MRSA in its pediatric community to be 0.8%1. Creech, et al., devised a study to describe the current prevalence of MRSA colonization in the same population.
The study population was children between the ages of two weeks and 21 years of age presenting for a health maintenance visit at two outpatient clinics. Nasal swabs were obtained and cultures preformed on plates with and without oxacillin containing media. Possible MRSA isolates were confirmed with PCR for the mecA gene, which codes for the protein responsible for beta-lactam resistance.
Of the 500 children enrolled 182 (36.4%) were found to be colonized with S. aureus. 46 (9.2%) isolates were positive for the mecA gene and considered MRSA. The only risk factor found to increase risk for MRSA colonization was having a family member who works in a hospital (odds ratio, 2.0; 95% confidence interval, 1.03-4.1). Fifty-four percent of MRSA isolates were resistant to erythromycin, and 32% of these had inducible clindamycin resistance.
Commentary: This study shows a greater than tenfold increase in MRSA colonization in a three-year time period in a healthy outpatient population. This finding is consistent with other studies that have shown increasing rates of colonization.2-3 This increase has led some institutions to attempt decolonization of MRSA, most often using nasal mupirocin. To determine if current evidence supports attempts to eradicate MRSA nasal colonization, the following literature search was performed: Cochrane DSR, ACP Journal Club, PubMed, and PubMed Clinical Queries were searched using the search terms “MRSA,” “colonization,” and “staphylococcus.”
One Cochrane review summarizes the evidence for use of antimicrobial agents on MRSA colonized patients4. Of six randomized controlled trials, only one compares rates of infection during follow-up between the study and control groups. The difference in infections was not statistically significant. Five other studies of inconsistent quality followed eradication rates of MRSA and varied widely in their results. The Cochrane review concluded that there was insufficient evidence to recommend nasal decolonization of MRSA.
One article reviewed the evidence for intranasal mupirocin for S. aureus.5 This review did not differentiate between MRSA and MSSA. The authors appraised clinical trials that evaluated the effect of mupirocin on MRSA colonization and infection. In a trial of patients undergoing dialysis there was no overall difference in the rate of infection between groups. In trials using mupirocin for preoperative prophylaxis there was no difference in number of surgical site infections. The authors concluded that mupirocin did not result in long-term clearance of S. aureus and that the available evidence does not support its use for prevention of infection. With the current evidence routine decolonization of patients colonized with MRSA cannot be recommended.
References
- Nakamura MM, Rohling KL, Shashaty M, et al. Prevalence of methicillin-resistant Staphylococcus aureus nasal carriage in the community pediatric population. Pediatr Infect Dis J. 2002;21:917-922.
- Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593-598.
- Fergie JE, Purcell K. Community-acquired methicillin-resistant Staphylococcus aureus infections in south Texas children. Pediatr Infect Dis J. 2001;20:860-863.
- Loeb M, Main C, Walker-Dilks C. Antimicrobial drugs for treating methicillin-resistant Staphylococcus aureus colonization. Cochrane Database Syst Rev. 2003;(4):CD003340.
- Laupland KB, Conly JM. Treatment of Staphylococcus aureus colonization and prophylaxis for infection with topical intranasal mupirocin: an evidence-based review. Clin Infect Dis. 2003;37:933-938.
Is Ultrasound Sufficient for Diagnosing Urolithiasis in the Pediatric Patient?
Palmer JS, Donaher ER, O’Riordan MA, et al. Diagnosis of Pediatric Urolithiasis: Role of ultrasound and computerized tomography. J Urol. 2005;174:1413-1416.
Review by Ann Mattison, RN, CPNP
Pediatric urolithiasis is uncommon and may present without the classic symptoms of renal colic, making diagnosis of pediatric urolithiasis problematic. Previously published data has revealed that unenhanced spiral CT is the gold standard in diagnosing urinary tract calculi in adults. However, CT carries the risk of exposure to ionizing radiation, which can be a significant issue in children.
Due to the low prevalence of urolithiasis in addition to concerns about radiation exposure, many primary care providers choose ultrasound as the initial radiographic study for children with symptoms that can be associated with urolithiasis, such as flank pain, abdominal pain, and gross hematuria. But the accuracy of ultrasound in detecting pediatric urolithiasis has not been well studied.
A retrospective chart review was performed in all patients 0-18 evaluated as outpatients and inpatients at the study institution. Subjects were identified by ICD-9 codes and billing records. The study showed the accuracy of ultrasounds performed was variable and dependent on the location of the calculi. In contrast, CT was highly accurate regardless of calculi location.
The study concluded that ultrasound may still be the appropriate initial study for the majority of children presenting with symptoms suggestive of urolithiasis; however, a negative ultrasound should not be considered sufficient to rule out the diagnosis of urolithiasis in pediatric patients. The authors recommended the patient with persistent symptoms and negative ultrasound undergo unenhanced CT. The retrospective design of this study limits application of these results; however, the study does highlight the need for a heightened index of suspicion for the diagnosis as well as the need for further prospective studies describing the most safe and efficient method for confirming the diagnosis. TH
The Tricky Nature of Medication Compliance
Review by Osterberg L, Blaschke T. Adherence to Medication. N Engl J Med. 2005;353:487-497.
Adherence to (or compliance with) a medication regimen is generally defined as the extent to which patients take medications as prescribed by their healthcare providers. Adherence rates are typically higher among patients with acute conditions, as compared with those with chronic conditions; persistence among patients with chronic conditions is disappointingly low, dropping most drastically after the first six months of therapy. Of all medication-related hospital admissions in the United States, 33% to 69% are because of poor medication adherence, with a resultant cost of approximately $100 billion a year.
Electronic medication-monitoring devices have provided very detailed information about the patterns of medication-taking behavior. Studies using these monitors have shown six general patterns of taking medication among patients treated for chronic illnesses who continue to take their medications. Approximately one-sixth come close to perfect adherence to a regimen; one-sixth take nearly all doses, but with some timing irregularity; one-sixth miss an occasional single day’s dose and have some timing inconsistency; one-sixth take drug holidays three to four times a year, with occasional omissions of doses; one-sixth have a drug holiday monthly or more often, with frequent omissions of doses; and one-sixth take few or no doses while giving the impression of good adherence.
Poor adherence to medication regimens is common, contributing to substantial worsening of disease, death, and increased healthcare costs. Practitioners should always look for poor adherence and can enhance adherence by emphasizing the value of a patient’s regimen, making the regimen simple, and customizing the regimen to the patient’s lifestyle. Asking patients nonjudgmentally about medication-taking behavior is a practical strategy for identifying poor adherence. A collaborative approach to care augments adherence. Patients who have difficulty maintaining adequate adherence need more intensive strategies than do patients who have less difficulty with adherence, a more forgiving medication regimen, or both. Innovative methods of managing chronic diseases have had some success in improving adherence when a regimen has been difficult to follow.
The New Clostridium Difficile—What Does It Mean?
McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxic gene-variant of Clostridium difficile. N Eng J Med. 2005;353;2433-2441.
Clostridium difficile is the only anaerobe that causes nosocomial infections. It colonizes the colon in 3% of the healthy population and about 20% to 40% of hospitalized patients.
This study was done in response to reports of increasing rate and severity of this infection. This study looked at healthcare facilities in Pennsylvania, Maine, Georgia, Oregon, Illinois, and New Jersey and did indeed find a new strain of Clostridium difficile isolate which showed 100% resistance to gatifloxacin and moxifloxacin, compared with no resistance in the historic strain.
Resistance to clindamycin was similar in both the groups, which was measured at 79%. This particular strain secretes 16 to 23 times more toxins A and B in vitro than other strains. And in this study the new strain accounted for 51% of the infections compared with 17% in the historic control isolates. Fluoroquinolones were implicated alone or in combination with other antibiotics in 52% of the cases. Those infected with the new strain were more likely to have higher rates of toxic megacolon, need for colectomy, leukemoid reaction, shock, and death. Like any disease, the interaction between host and pathogen is key to severity, thereby making patients who are chronically ill and elderly more susceptible.
For hospitalists the implications for this study are certainly important. We need to be aware of whether this strain is prevalent in our work environment. Close collaboration with our colleagues from infectious disease services along with monitoring clinical outcomes of patients with Clostridium difficile infection is the need of the hour. Also recommended is investigation of any increases in caseload of this infection. Simple measures such as judicious use of antibiotics, early diagnosis, and appropriate treatment of Clostridium difficile infection and strict isolation of the patients infected or colonized with Clostridium difficile would go a long way in controlling the spread of the new more virulent strain. It must be pointed out that alcohol-based waterless hand-sanitizing agents do not kill the Clostridium difficile spores; washing hands with soap and water is a prudent option after coming in contact with a patient with Clostridium difficile. TH
Nasal MRSA Carriage: A Study of Current Prevalence with Commentary
Creech CB, Kernodle DS, Alsectzer M, et al. Increasing rates of nasal carriage of methicillin-resistant Staphylococcus aureus in healthy children. Pediatr Infect Dis J. 2005;24:617-621.
Review by Laura Ortman, MD
The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections seen in outpatient clinics and emergency rooms appears to be on the rise. In 2001 a study done at Vanderbilt University Medical Center found the prevalence of MRSA in its pediatric community to be 0.8%1. Creech, et al., devised a study to describe the current prevalence of MRSA colonization in the same population.
The study population was children between the ages of two weeks and 21 years of age presenting for a health maintenance visit at two outpatient clinics. Nasal swabs were obtained and cultures preformed on plates with and without oxacillin containing media. Possible MRSA isolates were confirmed with PCR for the mecA gene, which codes for the protein responsible for beta-lactam resistance.
Of the 500 children enrolled 182 (36.4%) were found to be colonized with S. aureus. 46 (9.2%) isolates were positive for the mecA gene and considered MRSA. The only risk factor found to increase risk for MRSA colonization was having a family member who works in a hospital (odds ratio, 2.0; 95% confidence interval, 1.03-4.1). Fifty-four percent of MRSA isolates were resistant to erythromycin, and 32% of these had inducible clindamycin resistance.
Commentary: This study shows a greater than tenfold increase in MRSA colonization in a three-year time period in a healthy outpatient population. This finding is consistent with other studies that have shown increasing rates of colonization.2-3 This increase has led some institutions to attempt decolonization of MRSA, most often using nasal mupirocin. To determine if current evidence supports attempts to eradicate MRSA nasal colonization, the following literature search was performed: Cochrane DSR, ACP Journal Club, PubMed, and PubMed Clinical Queries were searched using the search terms “MRSA,” “colonization,” and “staphylococcus.”
One Cochrane review summarizes the evidence for use of antimicrobial agents on MRSA colonized patients4. Of six randomized controlled trials, only one compares rates of infection during follow-up between the study and control groups. The difference in infections was not statistically significant. Five other studies of inconsistent quality followed eradication rates of MRSA and varied widely in their results. The Cochrane review concluded that there was insufficient evidence to recommend nasal decolonization of MRSA.
One article reviewed the evidence for intranasal mupirocin for S. aureus.5 This review did not differentiate between MRSA and MSSA. The authors appraised clinical trials that evaluated the effect of mupirocin on MRSA colonization and infection. In a trial of patients undergoing dialysis there was no overall difference in the rate of infection between groups. In trials using mupirocin for preoperative prophylaxis there was no difference in number of surgical site infections. The authors concluded that mupirocin did not result in long-term clearance of S. aureus and that the available evidence does not support its use for prevention of infection. With the current evidence routine decolonization of patients colonized with MRSA cannot be recommended.
References
- Nakamura MM, Rohling KL, Shashaty M, et al. Prevalence of methicillin-resistant Staphylococcus aureus nasal carriage in the community pediatric population. Pediatr Infect Dis J. 2002;21:917-922.
- Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593-598.
- Fergie JE, Purcell K. Community-acquired methicillin-resistant Staphylococcus aureus infections in south Texas children. Pediatr Infect Dis J. 2001;20:860-863.
- Loeb M, Main C, Walker-Dilks C. Antimicrobial drugs for treating methicillin-resistant Staphylococcus aureus colonization. Cochrane Database Syst Rev. 2003;(4):CD003340.
- Laupland KB, Conly JM. Treatment of Staphylococcus aureus colonization and prophylaxis for infection with topical intranasal mupirocin: an evidence-based review. Clin Infect Dis. 2003;37:933-938.
Is Ultrasound Sufficient for Diagnosing Urolithiasis in the Pediatric Patient?
Palmer JS, Donaher ER, O’Riordan MA, et al. Diagnosis of Pediatric Urolithiasis: Role of ultrasound and computerized tomography. J Urol. 2005;174:1413-1416.
Review by Ann Mattison, RN, CPNP
Pediatric urolithiasis is uncommon and may present without the classic symptoms of renal colic, making diagnosis of pediatric urolithiasis problematic. Previously published data has revealed that unenhanced spiral CT is the gold standard in diagnosing urinary tract calculi in adults. However, CT carries the risk of exposure to ionizing radiation, which can be a significant issue in children.
Due to the low prevalence of urolithiasis in addition to concerns about radiation exposure, many primary care providers choose ultrasound as the initial radiographic study for children with symptoms that can be associated with urolithiasis, such as flank pain, abdominal pain, and gross hematuria. But the accuracy of ultrasound in detecting pediatric urolithiasis has not been well studied.
A retrospective chart review was performed in all patients 0-18 evaluated as outpatients and inpatients at the study institution. Subjects were identified by ICD-9 codes and billing records. The study showed the accuracy of ultrasounds performed was variable and dependent on the location of the calculi. In contrast, CT was highly accurate regardless of calculi location.
The study concluded that ultrasound may still be the appropriate initial study for the majority of children presenting with symptoms suggestive of urolithiasis; however, a negative ultrasound should not be considered sufficient to rule out the diagnosis of urolithiasis in pediatric patients. The authors recommended the patient with persistent symptoms and negative ultrasound undergo unenhanced CT. The retrospective design of this study limits application of these results; however, the study does highlight the need for a heightened index of suspicion for the diagnosis as well as the need for further prospective studies describing the most safe and efficient method for confirming the diagnosis. TH
The Tricky Nature of Medication Compliance
Review by Osterberg L, Blaschke T. Adherence to Medication. N Engl J Med. 2005;353:487-497.
Adherence to (or compliance with) a medication regimen is generally defined as the extent to which patients take medications as prescribed by their healthcare providers. Adherence rates are typically higher among patients with acute conditions, as compared with those with chronic conditions; persistence among patients with chronic conditions is disappointingly low, dropping most drastically after the first six months of therapy. Of all medication-related hospital admissions in the United States, 33% to 69% are because of poor medication adherence, with a resultant cost of approximately $100 billion a year.
Electronic medication-monitoring devices have provided very detailed information about the patterns of medication-taking behavior. Studies using these monitors have shown six general patterns of taking medication among patients treated for chronic illnesses who continue to take their medications. Approximately one-sixth come close to perfect adherence to a regimen; one-sixth take nearly all doses, but with some timing irregularity; one-sixth miss an occasional single day’s dose and have some timing inconsistency; one-sixth take drug holidays three to four times a year, with occasional omissions of doses; one-sixth have a drug holiday monthly or more often, with frequent omissions of doses; and one-sixth take few or no doses while giving the impression of good adherence.
Poor adherence to medication regimens is common, contributing to substantial worsening of disease, death, and increased healthcare costs. Practitioners should always look for poor adherence and can enhance adherence by emphasizing the value of a patient’s regimen, making the regimen simple, and customizing the regimen to the patient’s lifestyle. Asking patients nonjudgmentally about medication-taking behavior is a practical strategy for identifying poor adherence. A collaborative approach to care augments adherence. Patients who have difficulty maintaining adequate adherence need more intensive strategies than do patients who have less difficulty with adherence, a more forgiving medication regimen, or both. Innovative methods of managing chronic diseases have had some success in improving adherence when a regimen has been difficult to follow.
The New Clostridium Difficile—What Does It Mean?
McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxic gene-variant of Clostridium difficile. N Eng J Med. 2005;353;2433-2441.
Clostridium difficile is the only anaerobe that causes nosocomial infections. It colonizes the colon in 3% of the healthy population and about 20% to 40% of hospitalized patients.
This study was done in response to reports of increasing rate and severity of this infection. This study looked at healthcare facilities in Pennsylvania, Maine, Georgia, Oregon, Illinois, and New Jersey and did indeed find a new strain of Clostridium difficile isolate which showed 100% resistance to gatifloxacin and moxifloxacin, compared with no resistance in the historic strain.
Resistance to clindamycin was similar in both the groups, which was measured at 79%. This particular strain secretes 16 to 23 times more toxins A and B in vitro than other strains. And in this study the new strain accounted for 51% of the infections compared with 17% in the historic control isolates. Fluoroquinolones were implicated alone or in combination with other antibiotics in 52% of the cases. Those infected with the new strain were more likely to have higher rates of toxic megacolon, need for colectomy, leukemoid reaction, shock, and death. Like any disease, the interaction between host and pathogen is key to severity, thereby making patients who are chronically ill and elderly more susceptible.
For hospitalists the implications for this study are certainly important. We need to be aware of whether this strain is prevalent in our work environment. Close collaboration with our colleagues from infectious disease services along with monitoring clinical outcomes of patients with Clostridium difficile infection is the need of the hour. Also recommended is investigation of any increases in caseload of this infection. Simple measures such as judicious use of antibiotics, early diagnosis, and appropriate treatment of Clostridium difficile infection and strict isolation of the patients infected or colonized with Clostridium difficile would go a long way in controlling the spread of the new more virulent strain. It must be pointed out that alcohol-based waterless hand-sanitizing agents do not kill the Clostridium difficile spores; washing hands with soap and water is a prudent option after coming in contact with a patient with Clostridium difficile. TH
Nasal MRSA Carriage: A Study of Current Prevalence with Commentary
Creech CB, Kernodle DS, Alsectzer M, et al. Increasing rates of nasal carriage of methicillin-resistant Staphylococcus aureus in healthy children. Pediatr Infect Dis J. 2005;24:617-621.
Review by Laura Ortman, MD
The incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections seen in outpatient clinics and emergency rooms appears to be on the rise. In 2001 a study done at Vanderbilt University Medical Center found the prevalence of MRSA in its pediatric community to be 0.8%1. Creech, et al., devised a study to describe the current prevalence of MRSA colonization in the same population.
The study population was children between the ages of two weeks and 21 years of age presenting for a health maintenance visit at two outpatient clinics. Nasal swabs were obtained and cultures preformed on plates with and without oxacillin containing media. Possible MRSA isolates were confirmed with PCR for the mecA gene, which codes for the protein responsible for beta-lactam resistance.
Of the 500 children enrolled 182 (36.4%) were found to be colonized with S. aureus. 46 (9.2%) isolates were positive for the mecA gene and considered MRSA. The only risk factor found to increase risk for MRSA colonization was having a family member who works in a hospital (odds ratio, 2.0; 95% confidence interval, 1.03-4.1). Fifty-four percent of MRSA isolates were resistant to erythromycin, and 32% of these had inducible clindamycin resistance.
Commentary: This study shows a greater than tenfold increase in MRSA colonization in a three-year time period in a healthy outpatient population. This finding is consistent with other studies that have shown increasing rates of colonization.2-3 This increase has led some institutions to attempt decolonization of MRSA, most often using nasal mupirocin. To determine if current evidence supports attempts to eradicate MRSA nasal colonization, the following literature search was performed: Cochrane DSR, ACP Journal Club, PubMed, and PubMed Clinical Queries were searched using the search terms “MRSA,” “colonization,” and “staphylococcus.”
One Cochrane review summarizes the evidence for use of antimicrobial agents on MRSA colonized patients4. Of six randomized controlled trials, only one compares rates of infection during follow-up between the study and control groups. The difference in infections was not statistically significant. Five other studies of inconsistent quality followed eradication rates of MRSA and varied widely in their results. The Cochrane review concluded that there was insufficient evidence to recommend nasal decolonization of MRSA.
One article reviewed the evidence for intranasal mupirocin for S. aureus.5 This review did not differentiate between MRSA and MSSA. The authors appraised clinical trials that evaluated the effect of mupirocin on MRSA colonization and infection. In a trial of patients undergoing dialysis there was no overall difference in the rate of infection between groups. In trials using mupirocin for preoperative prophylaxis there was no difference in number of surgical site infections. The authors concluded that mupirocin did not result in long-term clearance of S. aureus and that the available evidence does not support its use for prevention of infection. With the current evidence routine decolonization of patients colonized with MRSA cannot be recommended.
References
- Nakamura MM, Rohling KL, Shashaty M, et al. Prevalence of methicillin-resistant Staphylococcus aureus nasal carriage in the community pediatric population. Pediatr Infect Dis J. 2002;21:917-922.
- Herold BC, Immergluck LC, Maranan MC, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593-598.
- Fergie JE, Purcell K. Community-acquired methicillin-resistant Staphylococcus aureus infections in south Texas children. Pediatr Infect Dis J. 2001;20:860-863.
- Loeb M, Main C, Walker-Dilks C. Antimicrobial drugs for treating methicillin-resistant Staphylococcus aureus colonization. Cochrane Database Syst Rev. 2003;(4):CD003340.
- Laupland KB, Conly JM. Treatment of Staphylococcus aureus colonization and prophylaxis for infection with topical intranasal mupirocin: an evidence-based review. Clin Infect Dis. 2003;37:933-938.
Is Ultrasound Sufficient for Diagnosing Urolithiasis in the Pediatric Patient?
Palmer JS, Donaher ER, O’Riordan MA, et al. Diagnosis of Pediatric Urolithiasis: Role of ultrasound and computerized tomography. J Urol. 2005;174:1413-1416.
Review by Ann Mattison, RN, CPNP
Pediatric urolithiasis is uncommon and may present without the classic symptoms of renal colic, making diagnosis of pediatric urolithiasis problematic. Previously published data has revealed that unenhanced spiral CT is the gold standard in diagnosing urinary tract calculi in adults. However, CT carries the risk of exposure to ionizing radiation, which can be a significant issue in children.
Due to the low prevalence of urolithiasis in addition to concerns about radiation exposure, many primary care providers choose ultrasound as the initial radiographic study for children with symptoms that can be associated with urolithiasis, such as flank pain, abdominal pain, and gross hematuria. But the accuracy of ultrasound in detecting pediatric urolithiasis has not been well studied.
A retrospective chart review was performed in all patients 0-18 evaluated as outpatients and inpatients at the study institution. Subjects were identified by ICD-9 codes and billing records. The study showed the accuracy of ultrasounds performed was variable and dependent on the location of the calculi. In contrast, CT was highly accurate regardless of calculi location.
The study concluded that ultrasound may still be the appropriate initial study for the majority of children presenting with symptoms suggestive of urolithiasis; however, a negative ultrasound should not be considered sufficient to rule out the diagnosis of urolithiasis in pediatric patients. The authors recommended the patient with persistent symptoms and negative ultrasound undergo unenhanced CT. The retrospective design of this study limits application of these results; however, the study does highlight the need for a heightened index of suspicion for the diagnosis as well as the need for further prospective studies describing the most safe and efficient method for confirming the diagnosis. TH
Magic Bullets
Patients with acute stroke or transient ischemic attack (TIA) should be admitted to a hospital for initial care and assessment; however, a substantial number of these patients will never be seen by a neurologist because of the limited number of physicians in this specialty area. Currently there is only one neurologist per 26,000 people in the United States, and most neurologists prefer to practice in the outpatient setting.1 According to one study, only 11.3% of stroke patients are attended exclusively by a neurologist.2 Hospitalists play a vital role in overcoming this lack of specialized care for stroke patients.
Pharmacotherapy
A significant body of evidence supports secondary prevention as a critical intervention strategy in reducing stroke risk. Identifying specific risk factors remains pivotal to successful secondary prevention. Managing hypertension, diabetes, and hyperlipidemia serves as an effective preventive role; however, preventive management with antithrombotic agents is an important part of the drug regimen for secondary prevention of recurrent ischemic stroke (IS).3
The choice of pharmacologic agents is based on stroke etiology. Anticoagulants such as warfarin are restricted to patients with stroke due to a cardioembolic source, whereas antiplatelet agents are mainly used to treat noncardioembolic and lacunar strokes.4 Currently, four oral antiplatelet agents may be used as therapy to prevent secondary IS: aspirin (acetylsalicylic acid or ASA), ticlopidine, clopidogrel, and ASA plus extended-release dipyridamole.
Aspirin
ASA is the most widely used and cost-effective antiplatelet agent. A salicylate, it blocks platelet activation by inhibiting the cyclo-oxygenase enzymes (COX-1 and COX-2). In several primary prevention trials ASA was associated with a statistically significant reduction in risk of first myocardial infarction (MI). Neither overall cardiovascular mortality nor total number of strokes was reduced by long-term ASA prophylaxis, however.5
ASA was shown to be effective in secondary prevention of noncardioembolic stroke (offering equivalent or better efficacy compared with warfarin) in the Stroke Prevention in Reversible Ischemia Trial and the Warfarin-Aspirin Recurrent Stroke Study.6 The Swedish Aspirin Low-Dose Trial, Dutch TIA Trial, and United Kingdom Transient Ischaemic Attack Aspirin Trial consistently demonstrated the efficacy and reduced gastric toxicity of low-dose ASA.7 A meta-analysis of 197 randomized trials versus control and 90 randomized comparisons between antiplatelet regimens show risk reduction with ASA of approximately 23% in combined vascular events (MI, stroke, and vascular death).8
Ticlopidine
Ticlopidine hydrochloride (thienopyridine) blocks platelet activation by inhibiting adenosine diphosphate-induced fibrinogen binding.7 Ticlopidine was superior to placebo and high-dose ASA in reducing the occurrence of stroke, MI, or vascular death in patients of both genders who had recent cerebral ischemia. This was demonstrated in two major phase 3 multicenter trials: the Ticlopidine Aspirin Stroke Study and the Canadian American Ticlopidine Study.9 Despite ticlopidine’s efficacy in these trials, the drug has been associated with severe adverse effects, including life-threatening neutropenia (1%) and thrombocytopenic purpura (one per 1,600 to 5,000 patients treated).3
Clopidogrel
The ticlopidine analogue clopidogrel is a potent inhibitor of platelet aggregation induced by adenosine diphosphate.7 The efficacy and safety of clopidogrel was evaluated in a randomized, double-blind, multicenter study—the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events trial, the largest clinical study of clopidogrel—of 19,000 patients with stroke, MI, or peripheral arterial disease.10
In this study, clopidogrel showed a more favorable safety and tolerability profile than ticlopidine; however, compared with ASA clopidogrel offered only a modest benefit of 8.7% for all cardiovascular events and showed no significant benefit over ASA for recurrent stroke.
Findings from two randomized trials—Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO)—have shown sustained benefits of clopidogrel for combined endpoints of MI, stroke, and vascular death.11-12 The incidence of stroke was very small and the risk of serious bleeding was significantly increased.
These trials provided the rationale to undertake the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke study (MATCH).13 This study was designed to determine whether the addition of ASA to clopidogrel would further reduce the risk of recurrent ischemic attacks in high-risk patients after recent IS or TIA, as was observed with coronary manifestations of atherothrombosis in the CURE and CREDO trials.
MATCH, a randomized, double-blind, placebo-controlled trial, involved 7,599 patients and compared clopidogrel with low-dose ASA plus clopidogrel. During an 18-month follow-up, no significant benefit was observed for ASA plus clopidogrel versus clopidogrel monotherapy; however, there was a significant increase in the risk of life-threatening bleeding in the group receiving combined therapy (2.6% versus 1.3%, respectively). Therefore, ASA plus clopidogrel is not a recommended option for prevention of secondary stroke in cerebrovascular patients.
STROKE
The scope of the problem
Stroke is one of the most significant health problems in the United States. Approximately 700,000 strokes and occur each year. Of these, 200,000 are recurrent strokes.18 Extensive studies have identified increasing age as the leading risk factor for stroke.16
Approximately 72% of stroke patients are older than 65; on average, patients with stroke tend to be older than patients with MI.4-19 Thus, the frequency of stroke will increase dramatically with lengthening of life expectancy and advancing age of our population.
A history of TIA poses another strong risk factor for stroke. Each year approximately 300,000 Americans suffer TIAs; about one-third of these people will develop a stroke.20-21 Risk factors include hypertension, cigarette smoking, diabetes mellitus, hyperlipidemia, obesity, and heart disease.—SS
ASA Plus Extended-Release Dipyridamole
The Second European Stroke Prevention Study (ESPS-2), a randomized trial with 2,500 patients, was conducted to compare the efficacy of ASA plus dipyridamole versus placebo. Dipyridamole is a pyrimidopyrimidine derivative from the papaverine family with antithrombotic properties and vasodilatory effects on cells and vasculature.14 It inhibits phosphodiesterases, resulting in increased concentration of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP), which inhibits platelet activation and adhesion.14
ESPS-2 results showed a 38% relative reduction in risk of stroke for the combination versus placebo. The study did not include an ASA-only group. Results prompted reformulation of dipyridamole into a high-dose extended-release capsule combined with low-dose ASA. The higher dose and slower release of dipyridamole combined with ASA provides a more consistent plasma level and is less affected by stomach acidity or concomitant medications.
This combination was tested versus ASA alone in the ESPS-2 trial.15 ESPS-2, a randomized, double-blind, multicenter study, enrolled 6,602 patients with prior stroke or TIA. During the two-year follow-up ASA plus extended-release dipyridamole reduced the risk of recurrent stroke by 37% compared with placebo, and by 22% compared with ASA or dipyridamole alone. Adverse events associated with this combination are similar to those observed with low-dose ASA.
These results were further substantiated by a recent post hoc analysis conducted using data from the ESPS-2 trial. ASA plus extended-release dipyridamole had greater efficacy in preventing stroke than ASA; this difference in efficacy was more pronounced in high-risk patients.16
We need further studies that include direct comparisons to verify the most effective and safe antiplatelet agent for secondary stroke prevention. The Prospective Regimen for Effectively Avoiding Second Strokes (PRoFESS) is a head-to-head trial designed to compare the combination of ASA plus extended-release dipyridamole to clopidogrel in terms of efficacy and safety. This study includes 15,500 patients in more than 20 countries at approximately 600 sites.17
Conclusions
Stroke remains a major public health concern. Hospitalists play a central role in stroke management by improving the overall quality of hospital care for stroke patients. Still, most residency programs don’t provide sufficient stroke education. Therefore, comprehensive neurology educational programs should be provided for hospitalists so they can provide efficient inpatient care; initiate effective secondary prevention strategies tailored to the specific needs of the patients, starting with appropriate antiplatelet therapy; monitor patients at poststroke rehabilitation centers during recovery period; and educate stroke patients and their caregivers about the disease and its risk factors.
Hospitalists can also initiate effective communication with outpatient primary care providers at the time of discharge to help ensure that the secondary prevention strategies initiated in the hospital are not only continued but strengthened. TH
Dr. Sachdeva is lead hospitalist in the Stroke Program at the Swedish Medical Center, Seattle, and clinical instructor at the University of Washington, Seattle.
References
- Kmietowicz Z. United Kingdom needs to double the number of neurologists. BMJ. 2001;322:1508.
- Ringel SP. The neurologist’s role in stroke management. Stroke. 1996; 27(11):1935-1936.
- Weinberger J. Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke. Drugs. 2005;65(4):461-471.
- Weinberger J. Managing and preventing ischemic stroke: Part II—risk assessment and prevention of secondary ischemic stroke. Clin Geriatr. 2004;12(8):41-46.
- Patrono C, Coller B, Dalen JF. Platelet-active drugs: the relationship among dose, effectiveness and side effects. Chest. 2001:119(suppl):39S-63S.
- Fayad P, Singh SP. Anti-thrombotic therapy for the secondary prevention of ischemic stroke. Chest. 2004;126(3):483S-512S.
- Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2001;119(suppl):300S-320S.
- Antiplatelet Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;12;324(7329):71-86.
- Robert S, Miller AJ, Fagan SC. Ticlopidine: a new antiplatelet agent for cerebrovascular disease. Pharmacotherapy. 1991;11(4):317-322.
- CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk for ischemic events. Lancet. 1996;348:1329-1339.
- Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
- Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420.
- Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337.
- European Stroke Prevention Study. ESPS Group. Stroke. 1990;21(8):1122-1130.20
- Diener HC, Cunha L, Forbes C, et al. European stroke prevention study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13.
- Sacco RL, Sivenius J, Diener HC. Efficacy of aspirin plus extended-release dipyridamole in preventing recurrent stroke in high-risk populations. Arch Neurol. 2005;62:403-408.
- PRoFESS Web site. Available at: www.profess-study.com/com/Main/newscentre/news_040604.jsp. Last accessed July 18, 2005
- Weinberger J. Managing and preventing ischemic stroke: Part I—risk assessment and treatment of primary ischemic stroke. Clin Geriatr. 2004;12(7):48-53.
- Heart Disease and Stroke Statistics—2005 Update. Dallas, Texas. American Heart Association; Dallas. 2005
- Johnston SC, Gress DR, Browner WS, et al. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000;284:2901-2906.
- Feinberg WM, Albers GW, Barnett H, et al. Guidelines for the management of transient ischemic attacks. Stroke. 1994;25:1320-1335.
Patients with acute stroke or transient ischemic attack (TIA) should be admitted to a hospital for initial care and assessment; however, a substantial number of these patients will never be seen by a neurologist because of the limited number of physicians in this specialty area. Currently there is only one neurologist per 26,000 people in the United States, and most neurologists prefer to practice in the outpatient setting.1 According to one study, only 11.3% of stroke patients are attended exclusively by a neurologist.2 Hospitalists play a vital role in overcoming this lack of specialized care for stroke patients.
Pharmacotherapy
A significant body of evidence supports secondary prevention as a critical intervention strategy in reducing stroke risk. Identifying specific risk factors remains pivotal to successful secondary prevention. Managing hypertension, diabetes, and hyperlipidemia serves as an effective preventive role; however, preventive management with antithrombotic agents is an important part of the drug regimen for secondary prevention of recurrent ischemic stroke (IS).3
The choice of pharmacologic agents is based on stroke etiology. Anticoagulants such as warfarin are restricted to patients with stroke due to a cardioembolic source, whereas antiplatelet agents are mainly used to treat noncardioembolic and lacunar strokes.4 Currently, four oral antiplatelet agents may be used as therapy to prevent secondary IS: aspirin (acetylsalicylic acid or ASA), ticlopidine, clopidogrel, and ASA plus extended-release dipyridamole.
Aspirin
ASA is the most widely used and cost-effective antiplatelet agent. A salicylate, it blocks platelet activation by inhibiting the cyclo-oxygenase enzymes (COX-1 and COX-2). In several primary prevention trials ASA was associated with a statistically significant reduction in risk of first myocardial infarction (MI). Neither overall cardiovascular mortality nor total number of strokes was reduced by long-term ASA prophylaxis, however.5
ASA was shown to be effective in secondary prevention of noncardioembolic stroke (offering equivalent or better efficacy compared with warfarin) in the Stroke Prevention in Reversible Ischemia Trial and the Warfarin-Aspirin Recurrent Stroke Study.6 The Swedish Aspirin Low-Dose Trial, Dutch TIA Trial, and United Kingdom Transient Ischaemic Attack Aspirin Trial consistently demonstrated the efficacy and reduced gastric toxicity of low-dose ASA.7 A meta-analysis of 197 randomized trials versus control and 90 randomized comparisons between antiplatelet regimens show risk reduction with ASA of approximately 23% in combined vascular events (MI, stroke, and vascular death).8
Ticlopidine
Ticlopidine hydrochloride (thienopyridine) blocks platelet activation by inhibiting adenosine diphosphate-induced fibrinogen binding.7 Ticlopidine was superior to placebo and high-dose ASA in reducing the occurrence of stroke, MI, or vascular death in patients of both genders who had recent cerebral ischemia. This was demonstrated in two major phase 3 multicenter trials: the Ticlopidine Aspirin Stroke Study and the Canadian American Ticlopidine Study.9 Despite ticlopidine’s efficacy in these trials, the drug has been associated with severe adverse effects, including life-threatening neutropenia (1%) and thrombocytopenic purpura (one per 1,600 to 5,000 patients treated).3
Clopidogrel
The ticlopidine analogue clopidogrel is a potent inhibitor of platelet aggregation induced by adenosine diphosphate.7 The efficacy and safety of clopidogrel was evaluated in a randomized, double-blind, multicenter study—the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events trial, the largest clinical study of clopidogrel—of 19,000 patients with stroke, MI, or peripheral arterial disease.10
In this study, clopidogrel showed a more favorable safety and tolerability profile than ticlopidine; however, compared with ASA clopidogrel offered only a modest benefit of 8.7% for all cardiovascular events and showed no significant benefit over ASA for recurrent stroke.
Findings from two randomized trials—Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO)—have shown sustained benefits of clopidogrel for combined endpoints of MI, stroke, and vascular death.11-12 The incidence of stroke was very small and the risk of serious bleeding was significantly increased.
These trials provided the rationale to undertake the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke study (MATCH).13 This study was designed to determine whether the addition of ASA to clopidogrel would further reduce the risk of recurrent ischemic attacks in high-risk patients after recent IS or TIA, as was observed with coronary manifestations of atherothrombosis in the CURE and CREDO trials.
MATCH, a randomized, double-blind, placebo-controlled trial, involved 7,599 patients and compared clopidogrel with low-dose ASA plus clopidogrel. During an 18-month follow-up, no significant benefit was observed for ASA plus clopidogrel versus clopidogrel monotherapy; however, there was a significant increase in the risk of life-threatening bleeding in the group receiving combined therapy (2.6% versus 1.3%, respectively). Therefore, ASA plus clopidogrel is not a recommended option for prevention of secondary stroke in cerebrovascular patients.
STROKE
The scope of the problem
Stroke is one of the most significant health problems in the United States. Approximately 700,000 strokes and occur each year. Of these, 200,000 are recurrent strokes.18 Extensive studies have identified increasing age as the leading risk factor for stroke.16
Approximately 72% of stroke patients are older than 65; on average, patients with stroke tend to be older than patients with MI.4-19 Thus, the frequency of stroke will increase dramatically with lengthening of life expectancy and advancing age of our population.
A history of TIA poses another strong risk factor for stroke. Each year approximately 300,000 Americans suffer TIAs; about one-third of these people will develop a stroke.20-21 Risk factors include hypertension, cigarette smoking, diabetes mellitus, hyperlipidemia, obesity, and heart disease.—SS
ASA Plus Extended-Release Dipyridamole
The Second European Stroke Prevention Study (ESPS-2), a randomized trial with 2,500 patients, was conducted to compare the efficacy of ASA plus dipyridamole versus placebo. Dipyridamole is a pyrimidopyrimidine derivative from the papaverine family with antithrombotic properties and vasodilatory effects on cells and vasculature.14 It inhibits phosphodiesterases, resulting in increased concentration of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP), which inhibits platelet activation and adhesion.14
ESPS-2 results showed a 38% relative reduction in risk of stroke for the combination versus placebo. The study did not include an ASA-only group. Results prompted reformulation of dipyridamole into a high-dose extended-release capsule combined with low-dose ASA. The higher dose and slower release of dipyridamole combined with ASA provides a more consistent plasma level and is less affected by stomach acidity or concomitant medications.
This combination was tested versus ASA alone in the ESPS-2 trial.15 ESPS-2, a randomized, double-blind, multicenter study, enrolled 6,602 patients with prior stroke or TIA. During the two-year follow-up ASA plus extended-release dipyridamole reduced the risk of recurrent stroke by 37% compared with placebo, and by 22% compared with ASA or dipyridamole alone. Adverse events associated with this combination are similar to those observed with low-dose ASA.
These results were further substantiated by a recent post hoc analysis conducted using data from the ESPS-2 trial. ASA plus extended-release dipyridamole had greater efficacy in preventing stroke than ASA; this difference in efficacy was more pronounced in high-risk patients.16
We need further studies that include direct comparisons to verify the most effective and safe antiplatelet agent for secondary stroke prevention. The Prospective Regimen for Effectively Avoiding Second Strokes (PRoFESS) is a head-to-head trial designed to compare the combination of ASA plus extended-release dipyridamole to clopidogrel in terms of efficacy and safety. This study includes 15,500 patients in more than 20 countries at approximately 600 sites.17
Conclusions
Stroke remains a major public health concern. Hospitalists play a central role in stroke management by improving the overall quality of hospital care for stroke patients. Still, most residency programs don’t provide sufficient stroke education. Therefore, comprehensive neurology educational programs should be provided for hospitalists so they can provide efficient inpatient care; initiate effective secondary prevention strategies tailored to the specific needs of the patients, starting with appropriate antiplatelet therapy; monitor patients at poststroke rehabilitation centers during recovery period; and educate stroke patients and their caregivers about the disease and its risk factors.
Hospitalists can also initiate effective communication with outpatient primary care providers at the time of discharge to help ensure that the secondary prevention strategies initiated in the hospital are not only continued but strengthened. TH
Dr. Sachdeva is lead hospitalist in the Stroke Program at the Swedish Medical Center, Seattle, and clinical instructor at the University of Washington, Seattle.
References
- Kmietowicz Z. United Kingdom needs to double the number of neurologists. BMJ. 2001;322:1508.
- Ringel SP. The neurologist’s role in stroke management. Stroke. 1996; 27(11):1935-1936.
- Weinberger J. Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke. Drugs. 2005;65(4):461-471.
- Weinberger J. Managing and preventing ischemic stroke: Part II—risk assessment and prevention of secondary ischemic stroke. Clin Geriatr. 2004;12(8):41-46.
- Patrono C, Coller B, Dalen JF. Platelet-active drugs: the relationship among dose, effectiveness and side effects. Chest. 2001:119(suppl):39S-63S.
- Fayad P, Singh SP. Anti-thrombotic therapy for the secondary prevention of ischemic stroke. Chest. 2004;126(3):483S-512S.
- Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2001;119(suppl):300S-320S.
- Antiplatelet Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;12;324(7329):71-86.
- Robert S, Miller AJ, Fagan SC. Ticlopidine: a new antiplatelet agent for cerebrovascular disease. Pharmacotherapy. 1991;11(4):317-322.
- CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk for ischemic events. Lancet. 1996;348:1329-1339.
- Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
- Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420.
- Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337.
- European Stroke Prevention Study. ESPS Group. Stroke. 1990;21(8):1122-1130.20
- Diener HC, Cunha L, Forbes C, et al. European stroke prevention study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13.
- Sacco RL, Sivenius J, Diener HC. Efficacy of aspirin plus extended-release dipyridamole in preventing recurrent stroke in high-risk populations. Arch Neurol. 2005;62:403-408.
- PRoFESS Web site. Available at: www.profess-study.com/com/Main/newscentre/news_040604.jsp. Last accessed July 18, 2005
- Weinberger J. Managing and preventing ischemic stroke: Part I—risk assessment and treatment of primary ischemic stroke. Clin Geriatr. 2004;12(7):48-53.
- Heart Disease and Stroke Statistics—2005 Update. Dallas, Texas. American Heart Association; Dallas. 2005
- Johnston SC, Gress DR, Browner WS, et al. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000;284:2901-2906.
- Feinberg WM, Albers GW, Barnett H, et al. Guidelines for the management of transient ischemic attacks. Stroke. 1994;25:1320-1335.
Patients with acute stroke or transient ischemic attack (TIA) should be admitted to a hospital for initial care and assessment; however, a substantial number of these patients will never be seen by a neurologist because of the limited number of physicians in this specialty area. Currently there is only one neurologist per 26,000 people in the United States, and most neurologists prefer to practice in the outpatient setting.1 According to one study, only 11.3% of stroke patients are attended exclusively by a neurologist.2 Hospitalists play a vital role in overcoming this lack of specialized care for stroke patients.
Pharmacotherapy
A significant body of evidence supports secondary prevention as a critical intervention strategy in reducing stroke risk. Identifying specific risk factors remains pivotal to successful secondary prevention. Managing hypertension, diabetes, and hyperlipidemia serves as an effective preventive role; however, preventive management with antithrombotic agents is an important part of the drug regimen for secondary prevention of recurrent ischemic stroke (IS).3
The choice of pharmacologic agents is based on stroke etiology. Anticoagulants such as warfarin are restricted to patients with stroke due to a cardioembolic source, whereas antiplatelet agents are mainly used to treat noncardioembolic and lacunar strokes.4 Currently, four oral antiplatelet agents may be used as therapy to prevent secondary IS: aspirin (acetylsalicylic acid or ASA), ticlopidine, clopidogrel, and ASA plus extended-release dipyridamole.
Aspirin
ASA is the most widely used and cost-effective antiplatelet agent. A salicylate, it blocks platelet activation by inhibiting the cyclo-oxygenase enzymes (COX-1 and COX-2). In several primary prevention trials ASA was associated with a statistically significant reduction in risk of first myocardial infarction (MI). Neither overall cardiovascular mortality nor total number of strokes was reduced by long-term ASA prophylaxis, however.5
ASA was shown to be effective in secondary prevention of noncardioembolic stroke (offering equivalent or better efficacy compared with warfarin) in the Stroke Prevention in Reversible Ischemia Trial and the Warfarin-Aspirin Recurrent Stroke Study.6 The Swedish Aspirin Low-Dose Trial, Dutch TIA Trial, and United Kingdom Transient Ischaemic Attack Aspirin Trial consistently demonstrated the efficacy and reduced gastric toxicity of low-dose ASA.7 A meta-analysis of 197 randomized trials versus control and 90 randomized comparisons between antiplatelet regimens show risk reduction with ASA of approximately 23% in combined vascular events (MI, stroke, and vascular death).8
Ticlopidine
Ticlopidine hydrochloride (thienopyridine) blocks platelet activation by inhibiting adenosine diphosphate-induced fibrinogen binding.7 Ticlopidine was superior to placebo and high-dose ASA in reducing the occurrence of stroke, MI, or vascular death in patients of both genders who had recent cerebral ischemia. This was demonstrated in two major phase 3 multicenter trials: the Ticlopidine Aspirin Stroke Study and the Canadian American Ticlopidine Study.9 Despite ticlopidine’s efficacy in these trials, the drug has been associated with severe adverse effects, including life-threatening neutropenia (1%) and thrombocytopenic purpura (one per 1,600 to 5,000 patients treated).3
Clopidogrel
The ticlopidine analogue clopidogrel is a potent inhibitor of platelet aggregation induced by adenosine diphosphate.7 The efficacy and safety of clopidogrel was evaluated in a randomized, double-blind, multicenter study—the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events trial, the largest clinical study of clopidogrel—of 19,000 patients with stroke, MI, or peripheral arterial disease.10
In this study, clopidogrel showed a more favorable safety and tolerability profile than ticlopidine; however, compared with ASA clopidogrel offered only a modest benefit of 8.7% for all cardiovascular events and showed no significant benefit over ASA for recurrent stroke.
Findings from two randomized trials—Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO)—have shown sustained benefits of clopidogrel for combined endpoints of MI, stroke, and vascular death.11-12 The incidence of stroke was very small and the risk of serious bleeding was significantly increased.
These trials provided the rationale to undertake the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke study (MATCH).13 This study was designed to determine whether the addition of ASA to clopidogrel would further reduce the risk of recurrent ischemic attacks in high-risk patients after recent IS or TIA, as was observed with coronary manifestations of atherothrombosis in the CURE and CREDO trials.
MATCH, a randomized, double-blind, placebo-controlled trial, involved 7,599 patients and compared clopidogrel with low-dose ASA plus clopidogrel. During an 18-month follow-up, no significant benefit was observed for ASA plus clopidogrel versus clopidogrel monotherapy; however, there was a significant increase in the risk of life-threatening bleeding in the group receiving combined therapy (2.6% versus 1.3%, respectively). Therefore, ASA plus clopidogrel is not a recommended option for prevention of secondary stroke in cerebrovascular patients.
STROKE
The scope of the problem
Stroke is one of the most significant health problems in the United States. Approximately 700,000 strokes and occur each year. Of these, 200,000 are recurrent strokes.18 Extensive studies have identified increasing age as the leading risk factor for stroke.16
Approximately 72% of stroke patients are older than 65; on average, patients with stroke tend to be older than patients with MI.4-19 Thus, the frequency of stroke will increase dramatically with lengthening of life expectancy and advancing age of our population.
A history of TIA poses another strong risk factor for stroke. Each year approximately 300,000 Americans suffer TIAs; about one-third of these people will develop a stroke.20-21 Risk factors include hypertension, cigarette smoking, diabetes mellitus, hyperlipidemia, obesity, and heart disease.—SS
ASA Plus Extended-Release Dipyridamole
The Second European Stroke Prevention Study (ESPS-2), a randomized trial with 2,500 patients, was conducted to compare the efficacy of ASA plus dipyridamole versus placebo. Dipyridamole is a pyrimidopyrimidine derivative from the papaverine family with antithrombotic properties and vasodilatory effects on cells and vasculature.14 It inhibits phosphodiesterases, resulting in increased concentration of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP), which inhibits platelet activation and adhesion.14
ESPS-2 results showed a 38% relative reduction in risk of stroke for the combination versus placebo. The study did not include an ASA-only group. Results prompted reformulation of dipyridamole into a high-dose extended-release capsule combined with low-dose ASA. The higher dose and slower release of dipyridamole combined with ASA provides a more consistent plasma level and is less affected by stomach acidity or concomitant medications.
This combination was tested versus ASA alone in the ESPS-2 trial.15 ESPS-2, a randomized, double-blind, multicenter study, enrolled 6,602 patients with prior stroke or TIA. During the two-year follow-up ASA plus extended-release dipyridamole reduced the risk of recurrent stroke by 37% compared with placebo, and by 22% compared with ASA or dipyridamole alone. Adverse events associated with this combination are similar to those observed with low-dose ASA.
These results were further substantiated by a recent post hoc analysis conducted using data from the ESPS-2 trial. ASA plus extended-release dipyridamole had greater efficacy in preventing stroke than ASA; this difference in efficacy was more pronounced in high-risk patients.16
We need further studies that include direct comparisons to verify the most effective and safe antiplatelet agent for secondary stroke prevention. The Prospective Regimen for Effectively Avoiding Second Strokes (PRoFESS) is a head-to-head trial designed to compare the combination of ASA plus extended-release dipyridamole to clopidogrel in terms of efficacy and safety. This study includes 15,500 patients in more than 20 countries at approximately 600 sites.17
Conclusions
Stroke remains a major public health concern. Hospitalists play a central role in stroke management by improving the overall quality of hospital care for stroke patients. Still, most residency programs don’t provide sufficient stroke education. Therefore, comprehensive neurology educational programs should be provided for hospitalists so they can provide efficient inpatient care; initiate effective secondary prevention strategies tailored to the specific needs of the patients, starting with appropriate antiplatelet therapy; monitor patients at poststroke rehabilitation centers during recovery period; and educate stroke patients and their caregivers about the disease and its risk factors.
Hospitalists can also initiate effective communication with outpatient primary care providers at the time of discharge to help ensure that the secondary prevention strategies initiated in the hospital are not only continued but strengthened. TH
Dr. Sachdeva is lead hospitalist in the Stroke Program at the Swedish Medical Center, Seattle, and clinical instructor at the University of Washington, Seattle.
References
- Kmietowicz Z. United Kingdom needs to double the number of neurologists. BMJ. 2001;322:1508.
- Ringel SP. The neurologist’s role in stroke management. Stroke. 1996; 27(11):1935-1936.
- Weinberger J. Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke. Drugs. 2005;65(4):461-471.
- Weinberger J. Managing and preventing ischemic stroke: Part II—risk assessment and prevention of secondary ischemic stroke. Clin Geriatr. 2004;12(8):41-46.
- Patrono C, Coller B, Dalen JF. Platelet-active drugs: the relationship among dose, effectiveness and side effects. Chest. 2001:119(suppl):39S-63S.
- Fayad P, Singh SP. Anti-thrombotic therapy for the secondary prevention of ischemic stroke. Chest. 2004;126(3):483S-512S.
- Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2001;119(suppl):300S-320S.
- Antiplatelet Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;12;324(7329):71-86.
- Robert S, Miller AJ, Fagan SC. Ticlopidine: a new antiplatelet agent for cerebrovascular disease. Pharmacotherapy. 1991;11(4):317-322.
- CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk for ischemic events. Lancet. 1996;348:1329-1339.
- Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
- Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420.
- Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337.
- European Stroke Prevention Study. ESPS Group. Stroke. 1990;21(8):1122-1130.20
- Diener HC, Cunha L, Forbes C, et al. European stroke prevention study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13.
- Sacco RL, Sivenius J, Diener HC. Efficacy of aspirin plus extended-release dipyridamole in preventing recurrent stroke in high-risk populations. Arch Neurol. 2005;62:403-408.
- PRoFESS Web site. Available at: www.profess-study.com/com/Main/newscentre/news_040604.jsp. Last accessed July 18, 2005
- Weinberger J. Managing and preventing ischemic stroke: Part I—risk assessment and treatment of primary ischemic stroke. Clin Geriatr. 2004;12(7):48-53.
- Heart Disease and Stroke Statistics—2005 Update. Dallas, Texas. American Heart Association; Dallas. 2005
- Johnston SC, Gress DR, Browner WS, et al. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000;284:2901-2906.
- Feinberg WM, Albers GW, Barnett H, et al. Guidelines for the management of transient ischemic attacks. Stroke. 1994;25:1320-1335.