PROTECT A coordinated stroke treatment program to prevent recurrent thromboembolic events B. Ovbiagele, MD; J.L. Saver, MD; A. Fredieu, MD; S. Suzuki, MD, PhD; N. McNair, RN; A. Dandekar, BS; T. Razinia, BS; and C.S. Kidwell, MD
Abstract—Objective: To assess the impact of the Preventing Recurrence of Thromboembolic Events through Coordinated Treatment (PROTECT) Program on achievement of its eight secondary prevention goals at the time of discharge. Methods: Achievement rates for the eight program goals at time of discharge were compared in all patients discharged from a university hospital-based stroke service with a diagnosis of ischemic stroke or TIA during a 1-year period after implementation of the PROTECT Program vs rates obtained from a comparable group of patients admitted to the same service during the preceding year. Results: Demographic and medical features were comparable in the baseline and intervention cohorts for all patients with cerebral ischemia presumed due to large-vessel atherosclerosis or small-vessel disease (baseline year n ⫽ 117, intervention n ⫽ 130). Implementation rates in patients without specific contraindications increased for all four medication goals: 97 to 100% for antithrombotic agents, 68 to 97% for statins, 42 to 90% for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 14 to 70% for diuretics. Although data were not collected on baseline lifestyle instruction rates, instruction in the program’s four lifestyle interventions was achieved by discharge in 100% of the intervention cohort. Conclusion: Implementation of this single-center, systems-based, inhospital program to initiate secondary stroke prevention therapies was associated with a substantial increase in treatment utilization at the time of hospital discharge. NEUROLOGY 2004;63:1217–1222
The majority of stroke risk factors are modifiable, and a variety of national guidelines, consensus statements, and systematic reviews have been developed to guide health professionals in the primary and secondary prevention of stroke.1-3 However, the implementation of stroke prevention strategies has been variable and suboptimal, resulting in a knowledge– implementation treatment gap.4-7 With a growing body of clinical trial evidence supporting secondary prevention strategies, it is more important than ever to find effective means to appropriately employ these treatments in everyday clinical practice. In other patient populations such as those with heart failure and coronary artery disease, studies have demonstrated that disease management programs initiated at the time of acute hospitalization result in higher utilization rates of long-term preven-
tion therapies as compared with patients managed conventionally.8 We therefore sought to develop and pilot an aggressive, hospital-based interdisciplinary stroke prevention treatment program, utilizing tools that reinforce adherence to key evidence-based therapies. The Preventing Recurrence of Thromboembolic Events through Coordinated Treatment (PROTECT) Program comprises a set of tools designed to achieve four medication and four lifestyle modification goals during the acute hospitalization for an ischemic cerebrovascular event. We sought to demonstrate the feasibility of integrating this program into routine inpatient stroke care as well as to assess the impact of the program on the initiation of secondary stroke prevention medications and education in lifestyle modification practices by the time of hospital discharge.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the October 12 issue to find the title link for this article.
Methods. Development of the Stroke PROTECT Program goals. Building upon the foundation of the highly successful Cardiac Hospitalization Atherosclerosis Management Program (CHAMP),8 but tailoring interventions specifically for the cerebrovascular
From the Stroke Center and Department of Neurology (Drs. Ovbiagele, Saver, Fredieu, Suzuki, and Kidwell, A. Dandekar and T. Razinia) and Department of Nursing (N. McNair), UCLA Medical Center, and Department of Neurology (Drs. Ovbiagele, Saver, Fredieu, Suzuki, and Kidwell), Olive View–UCLA Medical Center, Los Angeles, CA. Dr. Ovbiagele has acted as a paid scientific consultant for Bristol–Myers–Squibb and Sanofi Pharmaceuticals and has received speaker honoraria from Boehringer–Ingelheim. Dr. Saver has acted as a paid scientific consultant for Bristol–Myers–Squibb, Sanofi Pharmaceuticals, Boehringer–Ingelheim, and Wyeth and has received speaker honoraria from Bristol–Myers–Squibb and Sanofi Pharmaceuticals. Dr. Kidwell has acted as a paid scientific consultant for Bristol–Myers–Squibb and Sanofi Pharmaceuticals. Supported in part by NIH/National Institute of Neurologic Disorders and Stroke Award K23 NS 02088 (C.S.K.) and NIH/National Institute of Neurologic Disorders and Stroke Award K24 NS 02092 (J.L.S.). Funding for data collection within this study was supplied in part by unrestricted educational grants from Bristol–Myers–Squibb and Sanofi Pharmaceuticals. Received March 2, 2004. Accepted in final form May 19, 2004. Address correspondence and reprint requests to Dr. B. Ovbiagele, Stroke Center and Department of Neurology, University of California at Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095; e-mail:
[email protected] Copyright © 2004 by AAN Enterprises, Inc.
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Table 1 Stroke PROTECT Program goals Initiation and maintenance of appropriate: 1. Antithrombotic therapy 2. Statin therapy 3. Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy 4. Thiazide diuretic therapy 5. Smoking cessation advice and referral to a formal cessation program 6. American Heart Association diet 7. Exercise counseling 8. Stroke education including knowledge of stroke warning signs and need to call 911 in the event of a cerebrovascular event as well as awareness of individual’s own risk factors PROTECT ⫽ Preventing Recurrence of Thromboembolic Events through Coordinated Treatment. population, the PROTECT Program was designed to integrate proven secondary stroke prevention measures into the standard stroke care provided during the acute hospitalization. Its ultimate objective was to facilitate the early initiation and long-term maintenance of these measures in a systematic, expedient, and widely applicable manner, resulting in improved long-term treatment rates and vascular outcomes in all hospital patients admitted with a diagnosis of ischemic stroke or TIA. Development of program goals was guided by treatment algorithms derived from national clinical guidelines, consensus reports, and data from large clinical trials. The PROTECT protocol calls for the hospital initiation of eight interventions (table 1) in all patients with cerebral ischemia due to aortocervicocephalic atherosclerosis and a more limited set of tailored interventions in patients with other etiologies. Among the eight interventions, four target appropriate medication utilization and four target behavioral or lifestyle modification factors. The protocol specifies that the eight program goals be initiated in all ischemic stroke patients in whom the suspected underlying stroke mechanism is largevessel atherosclerosis, intracranial branch atherosclerosis, or lipohyalinosis (small-vessel disease).9 Atherosclerosis anywhere in the cervicocephalic arterial tree including within the aortic arch, cervical internal carotid artery, and intracranial large arteries and penetrating arteries qualifies the patient for the full PROTECT intervention. In patients with other mechanisms of stroke (cardioembolism, dissection, hypercoagulability, etc.), the program mandates the assessment and treatment of atherosclerotic risk factors, even if their index stroke is not clearly related to atherosclerosis (figure 1). Medication goals. Initiation and maintenance of appropriate antithrombotic therapy. The PROTECT antithrombotic guidelines incorporate the results of various antithrombotic trials10,11 and the American College of Chest Physicians (ACCP) and American Heart Association (AHA) guidelines12,13 to mandate that after noncardioembolic (atherothrombotic, lacunar) stroke or TIA, patients should receive daily antiplatelet therapy. For cardioembolic events, the ACCP and AHA guidelines direct that patients with atrial fibrillation receive long-term oral anticoagulation therapy (goal international normalized ratio 2.5, range 2.0 to 3.0) for stroke prevention after a recent stroke or TIA.12,13 Initiation and maintenance of a statin agent. The PROTECT algorithm (see figure E-1 on the Neurology Web site at www.neurology.org) dictates initiation of a statin in all patients with large- or small-vessel cerebral ischemic events, except in the unusual circumstance that the patient’s fasting total cholesterol level is below 135 mg/dL. This treatment strategy is based on the inclusion and exclusion criteria of the Heart Protection Study in which the patients enrolled with an index stroke showed a benefit homogeneous with the overall trial population,14 evidence from individual statin trials in patients with risk factors for or established coronary heart disease, and meta-analyses of these trials showing that stroke risk is reduced by statin agents.15-19 This goal is further sup1218
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Figure 1. Preventing Recurrence of Thromboembolic Events through Coordinated Treatment (PROTECT) Program: inpatient algorithm. ACE-I ⫽ angiotensinconverting enzyme inhibitor; ARB ⫽ angiotensin receptor blocker.
ported by studies showing a reduction in stroke risk through the measurement of biomarkers of cerebrovascular disease in high-risk individuals treated with statins.20-22 Initiation and maintenance of an antihypertensive agent. The PROTECT antihypertensives algorithm (see figure E-2 on the Neurology Web site) was derived from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines23 and the results of various trials that have shown the efficacy of angiotensin-converting enzyme (ACE) inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and thiazide diuretics in preventing strokes in individuals with hypertension24-30 and in nonhypertensive patients as well.27 JNC 7 recognizes that stroke is a “compelling indication” for combination antihypertensive therapy with an ACE inhibitor and thiazide diuretic, based on the results of Perindopril Protection Against Recurrent Stroke Study (PROGRESS). To this approach, the PROTECT algorithm permits the substitution of an ARB for an ACEI, based on the Losartan Intervention for Endpoint Reduction in Hypertension Study trial results. Based on PROGRESS, the PROTECT algorithm recognizes the benefits of combined therapy with ACEIs/ARBs and thiazide diuretics in patients with prehypertension in addition to patients with overt hypertension.26,27 Striking a balance between the desirability of starting antihypertensive therapy prior to discharge to enhance long-term compliance vs the need to avoid inducing neurologic worsening by overaggressive blood pressure lowering acutely, the PROTECT algorithm mandates antihypertensive initiation only after patients have been neurologically stable for a 48-hour period, at low dose, one agent at a time. Behavior modification and lifestyle goals. Smoking cessation advice and referral to a formal cessation program. Although 12 to 18% of strokes are attributable to active cigarette smoking, the stroke risk associated with former smoking has been shown to substantially decrease with increasing time since cessation.31 The Framingham Study found stroke risk to be at the level of nonsmokers at 5 years from cessation.32 Based on these and other cohort and epidemiologic studies, a consensus committee of healthcare professionals from the Stroke Council of the AHA has recommended immediate smoking cessation advice be given to all current smokers.31
Initiation and maintenance of the AHA diet. Based on various cohort studies, the AHA recommends a diet that includes fruits, vegetables, and fish as well as low quantities of cholesterol and saturated fat.33 Initiation of exercise counseling. There are well-established benefits of regular physical activity in stroke prevention.34,35 Guidelines endorsed by the AHA recommend that individuals should exercise moderately for at least 30 minutes on most and preferably all days of the week.36 Initiation and maintenance of stroke education, including awareness of stroke warning signs as well as instructions to call 911 in the event of a possible cerebrovascular event. Immediately after having an acute stroke, 43% of acute stroke patients in one study did not know a single sign or symptom of a stroke.37 Moreover, studies have demonstrated that even patients with a prior stroke or TIA frequently fail to present to the emergency room in a timely manner following a recurrent event.38 The National Stroke Association and other major health organizations have emphasized educating the public regarding the signs, symptoms, and risk factors for stroke.3 PROTECT Program tools and implementation. To facilitate implementation and utilization of the program, a variety of PROTECT Program tools were created and disseminated to neurology attending staff, primary care attending staff, fellows, resident staff, nursing staff, and additional health care professionals involved in the care of stroke patients throughout the medical center to foster understanding of the program’s rationale and enhance application of the program’s principles. These tools (see table E-1 on the Neurology Web site) included pocket cards, preprinted admission order sheets, medication algorithms, information sheets for both patients and primary card physicians, and a downloadable power-point slide set and were also made available on a PROTECT Program dedicated Web site (www.strokeprotect. mednet.ucla.edu). The pocket cards contained the goals of the program as well as the various classes and doses of the program’s medication interventions along with their contraindications, side effects, and precautions. Patient information sheets consisted of education materials on the progressive risks of atherosclerosis and the benefits of compliance with medical therapy and nonpharmacologic measures and were distributed to patients during the hospitalization. Preprinted admission orders were developed that included check boxes for ordering a lipid panel and for each of the recommended program therapies. Neuroscience nursing staff received educational “in-services” to encourage their role in providing patient counseling on risk factors during the stroke hospitalization. The interdisciplinary sheet was used by nurses and other health personnel to document that each case-appropriate PROTECT intervention had been implemented in each patient and to register that teaching and patient/family questions had been answered. Although treatment was strongly encouraged in the program guidelines and treatment algorithms, the final decision to initiate therapy and which agent and dose to use was decided by the individual treating physicians. The program was implemented at a university-based teaching hospital, which maintains a primary stroke service. Full-time stroke neurology and general neurology faculty serve as attending physicians supervising neurology house staff on the stroke service. In the actual implementation of the PROTECT Program, only existing personnel and resources were utilized. The only additional expenses were those allocated for data collection. For this study, data on consecutive patients were collected by the authors and analyzed for the first 12-month period of the program (April 1, 2002, to March 31, 2003). For comparison, data were also collected through record review by the authors, from a historical control cohort of consecutive patients encountered during the previous year (April 1, 2001, to March 31, 2002). During this time period, the stroke service attending physicians generally endorsed Stroke PROTECT goals based on clinical trial evidence and national guideline recommendations available at that time, but detailed systems-level interventions to achieve program goals were not in place. No patients were included in both the pre- and the postimplementation cohorts. Inclusion criteria for the study were 1) age ⱖ18 years and 2) admission to the stroke service with the diagnosis of ischemic stroke or TIA. Data abstracted from patient charts included patient demographics, stroke subtype per modified Trial of Org
Table 2 Clinical characteristics in pre-PROTECT and PROTECT overall cohorts Pre-PROTECT, 4/01–3/02; n ⫽ 216
PROTECT, 4/02–3/03; n ⫽ 230
70 (30–99)
73 (34–97)
97 (45)
99 (43)
White
164 (76)
184 (80)
Black
17 (8)
12 (5)
Asian
22 (10)
18 (8)
13 (6)
16 (7)
203 (94)
214 (93)
Variable Age (range), y Sex Female Race
Ethnicity Hispanic Non-Hispanic Past medical history Hypertension
149 (69)
154 (67)
Hypercholesterolemia
69 (32)
83 (36)
Stroke or TIA
58 (27)
67 (29)
Diabetes
58 (27)
60 (26)
CAD
56 (26)
64 (28)
Carotid stenosis ⬎50%
26 (12)
35 (15)
PAD
17 (8)
12 (5)
Current stroke/TIA subtype LV atherosclerosis
63 (29)
69 (30)
Small-vessel disease
62 (29)
58 (25)
Cardioembolism
67 (31)
69 (30)
Other
13 (6)
18 (8)
Undetermined
11 (5)
16 (7)
No variable was statistically different between the two cohorts. Values (except for age) are no. (%). PROTECT ⫽ Preventing Recurrence of Thromboembolic Events through Coordinated Treatment; CAD ⫽ coronary artery disease; PAD ⫽ peripheral artery disease; LV ⫽ large vessel.
10172 in Acute Stroke Treatment (TOAST) classification,39 and achievement by discharge of program goals. This study was approved by the University of California, Los Angeles, Institutional Review Board. Statistical analysis. Group differences in dichotomized endpoints were analyzed with the 2 test. Group differences in continuous endpoints were analyzed with the Student t-test.
Results. Demographics, past medical history, and clinical presentations. From April 2001 to March 2002 (prePROTECT historical controls), 216 consecutive men and women were hospitalized with a diagnosis of TIA or stroke, whereas from April 2002 to March 2003 (PROTECT cohort), 230 individuals were hospitalized with a diagnosis of TIA or stroke. There were no differences between the two groups with regard to a variety of baseline demographics and characteristics (table 2). However, a difference was noted between the number of individuals who had a lipid panel drawn, which was 80% in the pre-PROTECT group and 98% in the PROTECT group (p ⬍ 0.001). October (1 of 2) 2004
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Table 3 Overall cohort discharge utilization rates in both prePROTECT and PROTECT groups Pre-PROTECT, 4/01–3/02; n ⫽ 216
PROTECT, 4/02–3/03; n ⫽ 230
Antithrombotic
205 (95)
225 (98)
Statin
117 (54)
177 (77)
⬍0.001
ACEI/ARB
73 (34)
161 (70)
⬍0.001
Thiazide
26 (12)
85 (37)
⬍0.001
Therapy
Table 4 Reasons for non–medication implementation among target population (n ⫽ 130) in PROTECT period Agent
Reason for nonimplementation
No. (%)
p Statin 0.1403
Ineligibility by program protocol
4 (3)
Patient or family refusal
2 (2)
Total
6 (5)
Concerns for cerebral hypoperfusion
12 (9)
Mean arterial pressure ⬍75 mm Hg
4 (3)
Values are no. (%).
Symptomatic hypotension
2 (2)
PROTECT ⫽ Preventing Recurrence of Thromboembolic Events through Coordinated Treatment; ACEI ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensin receptor blocker.
Patient or family refusal
Discharge utilization rates. Medical therapy at the time of hospital discharge in the overall cohort changed substantially after the implementation of PROTECT, as shown in table 3. In the target population of individuals in the PROTECT cohort whose index stroke or TIA was due to large-artery atherosclerosis or likely intrinsic smallvessel disease, there was an even greater increase in utilization rates compared with the pre-PROTECT period, as depicted in figure 2. The commonest reason for nonmedication implementation for statins was drug contraindication, primarily elevated liver enzymes. The commonest reason for nonimplementation of antihypertensive agents by time of discharge was concern that inducing hypotension could precipitate neurologic worsening (table 4). The medical regimens instituted were fairly well tolerated in the PROTECT group. Program antihypertensive agents were discontinued prior to hospital discharge in 2 to 8% (see table 4) of the large- and small-vessel disease population owing to orthostatic lightheadedness or other systemic hypotensive symptoms. Education of patients in all four of the program’s lifestyle intervention goals was achieved by the time of hospital discharge in 100% of the PROTECT cohort.
Discussion. This study demonstrates that the PROTECT Program, a systematic, hospital-based secondary stroke prevention program, was associated with a substantial improvement in hospital discharge treatment utilization rates at our institution. Compared with a historical control cohort, in the
ACEI/ARB
Total Thiazide diuretic
2 (2) 20 (15)
Concerns for cerebral hypoperfusion
20 (15)
Mean arterial pressure ⬍75 mm Hg
10 (8)
Symptomatic hypotension
10 (8)
Patient or family refusal
2 (2)
Attending choice Total
2 (2) 44 (34)
PROTECT ⫽ Preventing Recurrence of Thromboembolic Events through Coordinated Treatment; ACEI ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensin receptor blocker.
target population of patients with likely atherosclerotic stroke mechanisms, medication utilization rates increased absolutely by 26 to 41% for the statin, diuretic, and ACEI/ARB interventions and by 100% for the antithrombotic intervention. Compared with large cohort studies,40,41 the PROTECT utilization rates for antithrombotics, smoking cessation education, and acute stroke warning sign education are among the highest ever reported in stroke patients. Similarly, rates of statin utilization in PROTECT patients were substantially higher than those reported in recent large clinical trials. The PROTECT Program differs from previous secondary stroke prevention initiatives in two ways: 1) its focus on the implementation of goals during the initial hospitalization and 2) an aggressive medication approach designed to slow or halt the underlying atherosclerotic process based on the most recent clinical trial evidence. It is well known that those who have just experienced a vascular event are at
Figure 2. Comparison of hospital discharge utilization rates in pre–Preventing Recurrence of Thromboembolic Events through Coordinated Treatment (PROTECT) target and PROTECT target groups for the four medication goals. Light blue columns ⫽ prePROTECT target control cohort (n ⫽ 117); lavender columns ⫽ PROTECT target cohort (n ⫽ 130); dark blue columns ⫽ PROTECT target cohort ⫺ individuals with specific protocol contraindications (n ⫽ 130, 126, 112, and 90). ACE-I ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensin receptor blocker. *†Analyses refer to comparison to Pre-Protect target control cohort. 1220
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extremely elevated risk for recurrent vascular events, particularly in the first days to weeks after the index event.42 The acute stroke hospitalization setting represents the ideal opportunity to institute evidence-based prevention therapies and education in behavioral modification strategies. The PROTECT Program helps to ensure that patients are not discharged from the hospital without initiation of secondary prevention measures proven to alter the natural history of atherosclerosis and decrease recurrent cerebrovascular events. The PROTECT strategy of in-hospital initiation of secondary prevention therapies contrasts with the common clinical practice in stroke patients of stroke specialists and hospitalist physicians focusing upon the acute management and diagnostic workup during the initial hospitalization and deferring start of long-term treatments, especially antihypertensives and statins, to the postdischarge setting, when the patient resumes long-term primary care follow-up. The deferred approach has several drawbacks. Therapy is initiated less efficiently weeks or months after the initial presentation, a time at which both patients and their primary care physicians may no longer be focused on the index stroke and the underlying atherosclerotic process. For patients, initiating medications during the acute stroke hospitalization sends the message that these therapies are important for the prevention of recurrent events and are an essential part of the treatment. For physicians, the initiation of medications, the scheduling of an outpatient appointment prior to discharge, a letter given to each patient detailing the reason for and importance of each medication, and a discharge “handoff” letter to posthospitalization providers outlining the rationale for the selected long-term secondary prevention therapies eliminate the miscommunications and misunderstandings that may occur between the neurologist and the generalist. Over the last decade, atherosclerosis has been increasingly recognized as a systemic disease, meriting aggressive, multimodal treatment irrespective of the particular vascular bed in which it first becomes manifest.43,44 Individuals with symptomatic lesions in one vascular bed often have additional asymptomatic atherosclerotic lesions in other vascular regions.45 Like the successful CHAMP8 and Get With the Guidelines—Heart Programs,46 PROTECT implements a multimodal treatment program for atherosclerosis that includes antithrombotics, statins, antihypertensives, diet, exercise, and tobacco cessation. The goal of these programs is to prevent all major consequences of atherosclerosis, including stroke, myocardial infarction, sudden vascular death, and limb claudication and amputation. This study has a number of limitations. As a historical control cohort was employed as a comparator group, some of the observed improvement may be due to a general trend toward higher goal implementation rates rather than a specific intervention effect. Furthermore, data abstractions were done by person-
nel aware of the program’s goals and not by independent audit. Another limitation is that due to a paucity of documentation pertaining to the collection and documentation of contraindications that might have led to noninitiation of specific medications (statins, antihypertensives), we were unable to generate a pre-PROTECT cohort without contraindications for optimal comparison. However, a comparison of the PROTECT cohort inclusive of contraindications vs the pre-PROTECT cohort (likely also inclusive of contraindications) depicts a substantial increase in statin and antihypertensive achievement rates at time of discharge. Future studies are required to demonstrate the impact of the PROTECT Program on long-term maintenance of target therapies, prevention of recurrent vascular events, and overall patient clinical outcome. The high implementation success rate in the PROTECT cohort was achieved in a single academic hospital with a primary stroke service. The program’s generalizability to community hospitals and different socioeconomic practice settings needs to be demonstrated. However, the PROTECT tool kit was specifically designed to allow it to be readily adopted and implemented in busy community hospitals and a variety of healthcare systems that may not run a primary stroke service. Expansion of the program into community hospitals is currently under way with plans to compare program utilization rates between the various types of hospitals. Acknowledgment The authors thank Greg Fonarow, MD, for his advice.
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