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Early Aggressive Medical Management for Patients with Symptomatic Intracranial Stenosis
Early Aggressive Medical Management for Patients with Symptomatic Intracranial Stenosis Fadi Nahab, MD,* Carlene Kingston, MD,* Michael R. Frankel, MD,* Jacques E. Dion, MD,* C. Michael Cawley, MD,* Brian Mitchell, MD,† L. Paige Hammonds, MSN,* Lauren Ayala, MSN,* and Frank C. Tong, MD*
Background: There are limited data on the effect of an early aggressive risk factor modification program to achieve risk factor targets and its impact on clinical outcomes among patients with symptomatic intracranial stenosis. Methods: We prospectively identified patients with symptomatic intracranial stenosis of 50% to 99% (using computed tomographic angiography or cerebral angiography) who failed to qualify for or declined to participate in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial but elected to receive aggressive medical management. Aggressive medical management was defined as aspirin plus clopidogrel therapy for a minimum of 3 months, blood pressure control, statin use with a low-density lipoprotein (LDL) goal of ,70 mg/dL, smoking cessation, and body mass index ,25 kg/m2. Results: Of 22 patients, the mean age was 65.6 6 7.7 years, 82% were male, 59% were white, and mean percent stenosis was 71.5 6 9.5% (55% with 70% to 99% stenosis). Median time from symptomatic event to first evaluation was 3 days. All patients completed 3 months of dual antiplatelet therapy, and at last follow-up, 86% had met their blood pressure goal, all were on statin therapy although only 73% had met their LDL goal, 96% reported no active tobacco use, and 36% had lost weight, but only 23% had achieved the BMI target. Over a mean follow-up of 1.2 years, there was no ischemic stroke, brain hemorrhage, or death from other vascular causes. Conclusions: An early aggressive risk factor modification program achieved high levels of blood pressure and cholesterol targets for patients with symptomatic intracranial stenosis and when combined with dual antiplatelet therapy was effective for the prevention of recurrent vascular events in this cohort. Key Words: Intracranial stenosis—medical therapy—risk factors—treatment. Ó 2013 by National Stroke Association
Symptomatic intracranial atherosclerosis is an important cause of strokes, especially among Asians, blacks, and Hispanics.1-3 Results of the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) study4 From the *Department of Neurology, Emory University, Atlanta; and †Athens Neurological Associates, Athens, Georgia. Received May 11, 2011; revision received June 14, 2011; accepted June 16, 2011. Address correspondence to Fadi Nahab, MD, Department of Neurology, Emory University, 1365 Clifton Rd, Clinic A 3rd Fl, A3429, Atlanta, GA 30322. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2011.06.012
found that these patients remained at high risk for recurrent stroke while taking aspirin or warfarin, with up to 18% having recurrent strokes in the territory of a 70% to 99% stenosis after 1 year.5 Prespecified analyses showed that being on versus off antithrombotic treatment at the time of the WASID qualifying event was not a predictor of recurrent stroke or death, and these results led to the suggestion that patients should not wait until failing antithrombotic therapy before consideration of treatment with intracranial stenting.6 However, in post-hoc analyses, the WASID trial identified medical factors other than antithrombotic therapy that were predictors of major vascular events. In multivariable analysis, systolic blood pressure $140 mm Hg
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(hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.27-2.52) and total cholesterol $200 mg/dL (HR 1.44; 95% CI 1.00-2.07) were associated with an increased risk of ischemic stroke, myocardial infarction (MI), or vascular death.7 Given that only 50% of WASID participants achieved an SBP ,140 mm Hg and only 63% of WASID participants achieved a total cholesterol ,200 mg/dL after 1 year of follow-up, the objectives of this study were to evaluate the ability of an early aggressive risk factor modification program to achieve risk factor targets rapidly among patients with symptomatic intracranial stenosis and to evaluate the risk of recurrent vascular events in a cohort of patients treated with early aggressive medical management.
Methods Study Design We prospectively identified all patients with an ischemic stroke or transient ischemic attack secondary to intracranial stenosis of 50% to 99% seen at Emory University Hospital or The Emory Clinic between July 1, 2008 and December 31, 2010 who failed to qualify for or declined to participate in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial but elected to receive aggressive medical management. All patients received computed tomographic angiography (CTA) or cerebral angiography examination, the results of which were reviewed by a single interventional neuroradiologist to measure the degree of stenosis according to WASID criteria.8 Patients with their last symptomatic event .3 months from first evaluation or with a nonatherosclerotic cause of stenosis, such as Moyamoya disease, dissection, or vasculitis, were excluded from this study.
Aggressive Medical Management Protocol Our protocol was modeled after the intensive medical therapy arm of the SAMMPRIS trial.9 All patients were placed on aspirin 325 mg daily and loaded with clopidogrel 300 to 600 mg daily with clopidogrel 75 mg daily continued for a minimum of 3 months. After 3 months, aspirin was reduced to 81 mg daily and clopidogrel 75 mg daily was continued unless patients reported cost difficulties or adverse events, at which time they were switched to aspirin monotherapy. Blood pressure medication was initiated no less than 24 hours after the symptomatic event with titration of medications every 2 to 4 weeks to achieve a target blood pressure ,140/90 mm Hg for nondiabetic and ,130/80 mm Hg for diabetic patients according to the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) guidelines.10 All patients were instructed to measure blood pressures twice a day (morning and evening) and
to maintain a log that they brought to each follow-up visit. A statin drug was initiated or adjusted on the initial day of evaluation if lipid panel results were not at goal. Statin choice and dose were selected to achieve target total cholesterol ,200 mg/dL and LDL cholesterol ,70 mg/dL without the need for additional titration and to achieve affordability for the patient. Active smokers at baseline received smoking cessation counseling and nicotine replacement therapy with medical therapy prescribed at the discretion of the provider. Diabetic patients with baseline hemoglobin A1c above 7% were referred to a specialty diabetes clinic for blood glucose management. All patients received dietary counseling by the provider at each visit and were advised to lose 1 pound per week to achieve a target body mass index of ,25 kg/m2. Dietary counseling was provided by the nurse practitioner or vascular neurologist at each visit. A 24-hour dietary recall was obtained from the patient at each visit. The provider instructed the patient on the components of the Mediterranean diet and used the 24-hour dietary recall to suggest ways to modify their diet. A handout describing the Mediterranean diet was provided to all patients on their first clinic visit.
Follow-up Patients were instructed to follow-up in the stroke clinic with a vascular neurologist or a nurse practitioner every 2 to 4 weeks until risk factors were at goal. A vascular neurologist evaluated all patients at 3 months of follow-up, and patients were subsequently seen by a vascular neurologist or their primary care physician every 3 to 6 months based on patient preference. At each visit, data on medication adherence, risk factor targets including recent laboratory results, and adverse events were obtained. All data were retrospectively collected by medical record review and telephone contact if the last follow-up had occurred beyond 3 months. The study was approved by the local institutional review board.
Statistical Analysis All data were presented as mean values 6 standard deviation for continuous data and frequencies for categorical data. Comparisons of achieved risk factor targets and clinical outcomes were made between our patient cohort and those of the WASID cohort4,7 using the Chi-square test for percentages. A 2-tailed P value # .05 was considered statistically significant.
Results During the 30-month study period, 22 patients met the study criteria. Their mean age was 65.6 6 7.7 years, 82% were male, 59% were white, and mean percent stenosis was 71.5 6 9.5% (55% with 70% to 99% stenosis; Table 1). Stroke was the symptomatic event in 14 (64%) patients.
AGGRESSIVE MEDICAL MANAGEMENT IN SYMPTOMATIC INTRACRANIAL STENOSIS
Table 1. Baseline characteristics of the study cohort Characteristic Age, y (mean 6 SD) Sex (% male) Race (% white) Qualifying event (% stroke) Location of stenosis (%) Internal carotid artery Middle cerebral artery Basilar Vertebral Baseline cerebral angiography (%) Mean % stenosis of affected artery (mean 6 SD) Stenosis $70% (%) Hypertension (%) Hyperlipidemia (%) Diabetes (%) Any smoking (%) Smoking at qualifying event (%) Antithrombotic at qualifying event (%) Aspirin plus clopidogrel
Study cohort (n 5 22) 65.6 6 7.7 18 (82) 13 (59) 14 (64) 1 (4.5) 7 (32) 10 (46) 4 (18) 15 (68) 71.5% 6 9.5% 12 (55) 20 (91) 22 (100) 10 (46) 11 (50) 4 (18) 11 (50) 0 (0)
Abbreviation: SD, standard deviation.
Median time from the symptomatic event to first evaluation was 3 days. Hypertension was present in 20 (91%) patients, hyperlipidemia in all patients, and diabetes in 10 (46%) patients; 9% of patients had a new diagnosis of hypertension, 23% had a new diagnosis of hyperlipidemia, and 18% had a new diagnosis of diabetes. All patients completed a minimum of 3 months of dual antiplatelet therapy, and 68% have remained on dual
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antiplatelet therapy (aspirin 81 mg, clopidogrel 75 mg) until last follow-up; no major hemorrhages occurred, although 7 patients were switched to aspirin monotherapy because of cost (n 5 4) or skin bruising (n 5 3). At the last follow-up, 86% had met their blood pressure goal, all were on statin therapy (although only 73% had met their LDL goal), and 96% reported no active tobacco use. Compared with the WASID cohort at year 2, our patients had significantly higher rates of blood pressure ,140 mm Hg (86 v 53%; P 5 .003) and LDL cholesterol ,70 mg/dL (73 v 10%; P 5 .0001; Table 2). Of patients with hypertension, 65% were taking a diuretic, 60% were taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 35% were taking a calcium channel blocker, 30% were taking a beta blocker, and 20% were taking clonidine at last follow-up. Overall, 14 (70%) of the hypertensive patients were on $2 antihypertensive medications. Of patients with hyperlipidemia, 11 (50%) were taking simvastatin, 7 (32%) were taking rosuvastatin, 3 were taking atorvastatin, and 1 (5%) was taking pravastatin. Of the 6 patients who had not achieved the LDL goal by last follow-up, 5 were not taking high-potency statins (atorvastatin or rosuvastatin) because of cost considerations, although they were taking maximum dosages of their statin. Overall, 13 (59%) patients were taking maximum dosages of their statin. Over a mean follow-up of 1.2 years (median 16.5 months), there was no ischemic stroke, brain hemorrhage, or vascular death. Compared to the WASID cohort (aspirin or warfarin) at 1 year of follow-up, our cohort had significantly lower rates of ischemic stroke, brain hemorrhage, or vascular death from other causes (0 v 16%; P 5 .035).
Table 2. Comparison of treatment and risk factor targets between the study cohort and WASID participants Characteristic
Study cohort (n 5 22)
WASID year 1* (n 5 365)
WASID year 2* (n 5 229)
Aspirin plus clopidogrel for $3 months (%) Median time from symptomatic event to first evaluation (days)
22 (100) 3
N/A N/A
N/A N/A
Systolic blood pressure ,140 mm Hg (%) Median time from symptomatic event to BP at goal (days) LDL,70 mg/dL (%) Median time from symptomatic event to LDL at goal (days) No active tobacco use (%) Diabetics with A1c #7.0% (%) BMI #25 (%)
Baseline
Last follow-up
9 (41) 14
19 (86)
182 (50) N/A
121 (53) N/A
8 (36) 30
16 (73)
44 (12) N/A
23 (10) N/A
18 (82) 7 (70) 7 (32)
21 (96) 7 (70) 5 (23)
303 (83) 161 (44) N/A
192 (84) 97 (42) N/A
Abbreviations: BP, blood pressure; BMI, body mass index; LDL, low-density lipoprotein; N/A, not available; WASID, Warfarin versus Aspirin for Symptomatic Intracranial Disease. *See Chaturvedi et al.7
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Discussion We found that a stroke clinic–based risk factor modification program can achieve high levels of blood pressure and LDL cholesterol targets for patients with symptomatic intracranial stenosis. In addition, dual antiplatelet therapy with aspirin and clopidogrel combined with early aggressive medical management was effective for the prevention of recurrent vascular events. Our results are consistent with those reported in the clinical alert by the National Institute of Neurological Disorders and Stroke (NINDS), which recently stopped additional trial enrollment in the SAMMPRIS trial because of a higher 30-day risk of stroke and death among participants randomized to the stenting arm than those in the intensive medical therapy arm alone.11 The 30-day risk of stroke or death in the intensive medical therapy arm of SAMMPRIS was only 5.8%—substantially lower than the estimated rate of 10.7% based on historical controls who received standard medical care. These results have important implications in the management of patients with symptomatic intracranial stenosis. Our early aggressive medical management protocol was modeled after the intensive medical therapy arm of SAMMPRIS with the exception that our cohort was continued on dual antiplatelet therapy (aspirin 81 mg and clopidogrel 75 mg daily) beyond 3 months. We chose this dual antiplatelet regimen for several reasons: first, the WASID trial revealed that ischemic cerebrovascular events as opposed to hemorrhagic cerebrovascular events made up the majority of recurrent vascular events; second, in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, 77% of the cohort (n 5 12,153) were ‘‘symptomatic’’ patients (with documented coronary disease, cerebrovascular disease, or peripheral arterial disease) and those randomized to dual clopidogrel plus aspirin therapy had a significantly lower rate of MI, stroke, or cardiovascular death compared to aspirin monotherapy (6.9% v 7.9%; relative risk 0.88; 95% CI 0.77-0.998; P 5 .046) with no significant increase in severe bleeding among ‘‘symptomatic’’ patients (1.6% v 1.4%; P 5 .39) and no increased risk of cardiovascular death or all-cause mortality12; third, while the Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH) trial found that dual antiplatelet therapy was of no benefit when compared with clopidogrel monotherapy among patients with stroke or transient ischemic attack and associated with a small but significant increase in the risk of life-threatening bleeding (absolute risk increase of 1.3% over 18 months of follow-up),13 only one-third of MATCH trial patients had large vessel atherosclerosis as their mechanism of stroke, and of these, only 5% had a history of MI, much lower than previously described for this population.14 We agree with others who have questioned whether the MATCH results can be
extrapolated to patients with ischemic stroke secondary to large vessel atherosclerosis.14 Therefore, we recommend that these patients remain on long-term dual antiplatelet therapy with low-dose aspirin and clopidogrel unless they have an increased risk of bleeding (severe hepatic insufficiency, current peptic ulceration, history of systemic bleeding, or other history of coagulopathy). Another important implication of our study and the preliminary results of the SAMMPRIS trial relates to the optimal time when patients should be considered for stenting. While data from the WASID study suggest that antithrombotic ‘‘failure’’ at the qualifying event was not a predictor of recurrent stroke or vascular death, our results and those of the SAMMPRIS trial would suggest that intracranial stenting should be considered only after patients fail early aggressive medical management. Given that our current study reveals that high levels of risk factor targets can be achieved outside of a clinical trial setting, this approach may also be more cost effective given the high hospitalization charges among patients who undergo primary angioplasty or angioplasty-stenting when compared with ischemic stroke patients who do not undergo this procedure.15 Limitations of our study include the small sample size and relatively short follow-up. We were unable to include a control group treated with usual medical treatment because of the small sample size. While the patients were prospectively identified, data collection was obtained retrospectively. In addition, our study identified no patients who failed early aggressive medical management or had hypoperfusion as the primary mechanism of stroke in the territory, subgroups which may benefit from primary angioplasty or angioplasty-stenting.
References 1. Sacco RL, Kargman DE, Gu Q, et al. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. Stroke 1995;26:14-20. 2. Wityk RJ, Lehman D, Klag M, et al. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996;27:1974-1980. 3. Feldmann E, Daneault N, Kwan E, et al. Chinese-white differences in the distribution of occlusive cerebrovascular disease. Neurology 1990;40:1541-1545. 4. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Warfarin-Aspirin Symptomatic Intracranial Disease Trial. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352:1305-1316. 5. Kasner SE, Chimowitz MI, Lynn MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006;113:555-563. 6. Turan TN, Maidan L, Cotsonis G, et al. Failure of antithrombotic therapy and risk of stroke in patients with symptomatic intracranial stenosis. Stroke 2009;40:505-509. 7. Chaturvedi S, Turan TN, Lynn MJ, et al. Risk factor status and vascular events in patients with symptomatic intracranial stenosis. Neurology 2007;69:2063-2068.
AGGRESSIVE MEDICAL MANAGEMENT IN SYMPTOMATIC INTRACRANIAL STENOSIS 8. Samuels OB, Joseph GJ, Lynn MJ, et al. A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol 2000;21:643-646. 9. Chimowitz MI, Lynn MJ, Turan TN, et al. Design of the stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis trial. J Stroke Cerebrovasc Dis 2011;20:357-368. 10. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003;289:2560-2572. 11. Clinical Alert: Angioplasty combined with stenting plus aggressive medical therapy vs. aggressive medical therapy for intracranial arterial stenosis: NINDS stops trial enrollment due to a higher risk of stroke and death in the stented group. Available from: http://www.nlm.nih. gov/databases/alerts/intracranial_arterial_stenosis.html. Accessed April 30, 2011.
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12. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354: 1706-1717. 13. 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): Randomized, double-blind, placebo-controlled trial. Lancet 2004; 364:331-337. 14. Amarenco P, Donnan GA. Should the MATCH results be extrapolated to all stroke patients and affect ongoing trials evaluating clopidogrel plus aspirin? Stroke 2004; 35:2606-2608. 15. Mohammad YM, Chaudry S, Vazquez G, et al. Intracranial angioplasty and/or stent placement in general practice. An analysis of 370,061 patient admissions with ischemic stroke. Stroke 2011;42:e78.
Background: There are limited data on the effect of an early aggressive risk factor modification program to achieve risk factor targets and its impact on clinical outcomes among patients with symptomatic intracranial stenosis. Methods: We prospectively identified patients with symptomatic intracranial stenosis of 50% to 99% (using computed tomographic angiography or cerebral angiography) who failed to qualify for or declined to participate in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial but elected to receive aggressive medical management. Aggressive medical management was defined as aspirin plus clopidogrel therapy for a minimum of 3 months, blood pressure control, statin use with a low-density lipoprotein (LDL) goal of ,70 mg/dL, smoking cessation, and body mass index ,25 kg/m2. Results: Of 22 patients, the mean age was 65.6 6 7.7 years, 82% were male, 59% were white, and mean percent stenosis was 71.5 6 9.5% (55% with 70% to 99% stenosis). Median time from symptomatic event to first evaluation was 3 days. All patients completed 3 months of dual antiplatelet therapy, and at last follow-up, 86% had met their blood pressure goal, all were on statin therapy although only 73% had met their LDL goal, 96% reported no active tobacco use, and 36% had lost weight, but only 23% had achieved the BMI target. Over a mean follow-up of 1.2 years, there was no ischemic stroke, brain hemorrhage, or death from other vascular causes. Conclusions: An early aggressive risk factor modification program achieved high levels of blood pressure and cholesterol targets for patients with symptomatic intracranial stenosis and when combined with dual antiplatelet therapy was effective for the prevention of recurrent vascular events in this cohort. Key Words: Intracranial stenosis—medical therapy—risk factors—treatment. Ó 2013 by National Stroke Association
Symptomatic intracranial atherosclerosis is an important cause of strokes, especially among Asians, blacks, and Hispanics.1-3 Results of the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) study4 From the *Department of Neurology, Emory University, Atlanta; and †Athens Neurological Associates, Athens, Georgia. Received May 11, 2011; revision received June 14, 2011; accepted June 16, 2011. Address correspondence to Fadi Nahab, MD, Department of Neurology, Emory University, 1365 Clifton Rd, Clinic A 3rd Fl, A3429, Atlanta, GA 30322. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2011.06.012
found that these patients remained at high risk for recurrent stroke while taking aspirin or warfarin, with up to 18% having recurrent strokes in the territory of a 70% to 99% stenosis after 1 year.5 Prespecified analyses showed that being on versus off antithrombotic treatment at the time of the WASID qualifying event was not a predictor of recurrent stroke or death, and these results led to the suggestion that patients should not wait until failing antithrombotic therapy before consideration of treatment with intracranial stenting.6 However, in post-hoc analyses, the WASID trial identified medical factors other than antithrombotic therapy that were predictors of major vascular events. In multivariable analysis, systolic blood pressure $140 mm Hg
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(hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.27-2.52) and total cholesterol $200 mg/dL (HR 1.44; 95% CI 1.00-2.07) were associated with an increased risk of ischemic stroke, myocardial infarction (MI), or vascular death.7 Given that only 50% of WASID participants achieved an SBP ,140 mm Hg and only 63% of WASID participants achieved a total cholesterol ,200 mg/dL after 1 year of follow-up, the objectives of this study were to evaluate the ability of an early aggressive risk factor modification program to achieve risk factor targets rapidly among patients with symptomatic intracranial stenosis and to evaluate the risk of recurrent vascular events in a cohort of patients treated with early aggressive medical management.
Methods Study Design We prospectively identified all patients with an ischemic stroke or transient ischemic attack secondary to intracranial stenosis of 50% to 99% seen at Emory University Hospital or The Emory Clinic between July 1, 2008 and December 31, 2010 who failed to qualify for or declined to participate in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial but elected to receive aggressive medical management. All patients received computed tomographic angiography (CTA) or cerebral angiography examination, the results of which were reviewed by a single interventional neuroradiologist to measure the degree of stenosis according to WASID criteria.8 Patients with their last symptomatic event .3 months from first evaluation or with a nonatherosclerotic cause of stenosis, such as Moyamoya disease, dissection, or vasculitis, were excluded from this study.
Aggressive Medical Management Protocol Our protocol was modeled after the intensive medical therapy arm of the SAMMPRIS trial.9 All patients were placed on aspirin 325 mg daily and loaded with clopidogrel 300 to 600 mg daily with clopidogrel 75 mg daily continued for a minimum of 3 months. After 3 months, aspirin was reduced to 81 mg daily and clopidogrel 75 mg daily was continued unless patients reported cost difficulties or adverse events, at which time they were switched to aspirin monotherapy. Blood pressure medication was initiated no less than 24 hours after the symptomatic event with titration of medications every 2 to 4 weeks to achieve a target blood pressure ,140/90 mm Hg for nondiabetic and ,130/80 mm Hg for diabetic patients according to the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) guidelines.10 All patients were instructed to measure blood pressures twice a day (morning and evening) and
to maintain a log that they brought to each follow-up visit. A statin drug was initiated or adjusted on the initial day of evaluation if lipid panel results were not at goal. Statin choice and dose were selected to achieve target total cholesterol ,200 mg/dL and LDL cholesterol ,70 mg/dL without the need for additional titration and to achieve affordability for the patient. Active smokers at baseline received smoking cessation counseling and nicotine replacement therapy with medical therapy prescribed at the discretion of the provider. Diabetic patients with baseline hemoglobin A1c above 7% were referred to a specialty diabetes clinic for blood glucose management. All patients received dietary counseling by the provider at each visit and were advised to lose 1 pound per week to achieve a target body mass index of ,25 kg/m2. Dietary counseling was provided by the nurse practitioner or vascular neurologist at each visit. A 24-hour dietary recall was obtained from the patient at each visit. The provider instructed the patient on the components of the Mediterranean diet and used the 24-hour dietary recall to suggest ways to modify their diet. A handout describing the Mediterranean diet was provided to all patients on their first clinic visit.
Follow-up Patients were instructed to follow-up in the stroke clinic with a vascular neurologist or a nurse practitioner every 2 to 4 weeks until risk factors were at goal. A vascular neurologist evaluated all patients at 3 months of follow-up, and patients were subsequently seen by a vascular neurologist or their primary care physician every 3 to 6 months based on patient preference. At each visit, data on medication adherence, risk factor targets including recent laboratory results, and adverse events were obtained. All data were retrospectively collected by medical record review and telephone contact if the last follow-up had occurred beyond 3 months. The study was approved by the local institutional review board.
Statistical Analysis All data were presented as mean values 6 standard deviation for continuous data and frequencies for categorical data. Comparisons of achieved risk factor targets and clinical outcomes were made between our patient cohort and those of the WASID cohort4,7 using the Chi-square test for percentages. A 2-tailed P value # .05 was considered statistically significant.
Results During the 30-month study period, 22 patients met the study criteria. Their mean age was 65.6 6 7.7 years, 82% were male, 59% were white, and mean percent stenosis was 71.5 6 9.5% (55% with 70% to 99% stenosis; Table 1). Stroke was the symptomatic event in 14 (64%) patients.
AGGRESSIVE MEDICAL MANAGEMENT IN SYMPTOMATIC INTRACRANIAL STENOSIS
Table 1. Baseline characteristics of the study cohort Characteristic Age, y (mean 6 SD) Sex (% male) Race (% white) Qualifying event (% stroke) Location of stenosis (%) Internal carotid artery Middle cerebral artery Basilar Vertebral Baseline cerebral angiography (%) Mean % stenosis of affected artery (mean 6 SD) Stenosis $70% (%) Hypertension (%) Hyperlipidemia (%) Diabetes (%) Any smoking (%) Smoking at qualifying event (%) Antithrombotic at qualifying event (%) Aspirin plus clopidogrel
Study cohort (n 5 22) 65.6 6 7.7 18 (82) 13 (59) 14 (64) 1 (4.5) 7 (32) 10 (46) 4 (18) 15 (68) 71.5% 6 9.5% 12 (55) 20 (91) 22 (100) 10 (46) 11 (50) 4 (18) 11 (50) 0 (0)
Abbreviation: SD, standard deviation.
Median time from the symptomatic event to first evaluation was 3 days. Hypertension was present in 20 (91%) patients, hyperlipidemia in all patients, and diabetes in 10 (46%) patients; 9% of patients had a new diagnosis of hypertension, 23% had a new diagnosis of hyperlipidemia, and 18% had a new diagnosis of diabetes. All patients completed a minimum of 3 months of dual antiplatelet therapy, and 68% have remained on dual
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antiplatelet therapy (aspirin 81 mg, clopidogrel 75 mg) until last follow-up; no major hemorrhages occurred, although 7 patients were switched to aspirin monotherapy because of cost (n 5 4) or skin bruising (n 5 3). At the last follow-up, 86% had met their blood pressure goal, all were on statin therapy (although only 73% had met their LDL goal), and 96% reported no active tobacco use. Compared with the WASID cohort at year 2, our patients had significantly higher rates of blood pressure ,140 mm Hg (86 v 53%; P 5 .003) and LDL cholesterol ,70 mg/dL (73 v 10%; P 5 .0001; Table 2). Of patients with hypertension, 65% were taking a diuretic, 60% were taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 35% were taking a calcium channel blocker, 30% were taking a beta blocker, and 20% were taking clonidine at last follow-up. Overall, 14 (70%) of the hypertensive patients were on $2 antihypertensive medications. Of patients with hyperlipidemia, 11 (50%) were taking simvastatin, 7 (32%) were taking rosuvastatin, 3 were taking atorvastatin, and 1 (5%) was taking pravastatin. Of the 6 patients who had not achieved the LDL goal by last follow-up, 5 were not taking high-potency statins (atorvastatin or rosuvastatin) because of cost considerations, although they were taking maximum dosages of their statin. Overall, 13 (59%) patients were taking maximum dosages of their statin. Over a mean follow-up of 1.2 years (median 16.5 months), there was no ischemic stroke, brain hemorrhage, or vascular death. Compared to the WASID cohort (aspirin or warfarin) at 1 year of follow-up, our cohort had significantly lower rates of ischemic stroke, brain hemorrhage, or vascular death from other causes (0 v 16%; P 5 .035).
Table 2. Comparison of treatment and risk factor targets between the study cohort and WASID participants Characteristic
Study cohort (n 5 22)
WASID year 1* (n 5 365)
WASID year 2* (n 5 229)
Aspirin plus clopidogrel for $3 months (%) Median time from symptomatic event to first evaluation (days)
22 (100) 3
N/A N/A
N/A N/A
Systolic blood pressure ,140 mm Hg (%) Median time from symptomatic event to BP at goal (days) LDL,70 mg/dL (%) Median time from symptomatic event to LDL at goal (days) No active tobacco use (%) Diabetics with A1c #7.0% (%) BMI #25 (%)
Baseline
Last follow-up
9 (41) 14
19 (86)
182 (50) N/A
121 (53) N/A
8 (36) 30
16 (73)
44 (12) N/A
23 (10) N/A
18 (82) 7 (70) 7 (32)
21 (96) 7 (70) 5 (23)
303 (83) 161 (44) N/A
192 (84) 97 (42) N/A
Abbreviations: BP, blood pressure; BMI, body mass index; LDL, low-density lipoprotein; N/A, not available; WASID, Warfarin versus Aspirin for Symptomatic Intracranial Disease. *See Chaturvedi et al.7
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Discussion We found that a stroke clinic–based risk factor modification program can achieve high levels of blood pressure and LDL cholesterol targets for patients with symptomatic intracranial stenosis. In addition, dual antiplatelet therapy with aspirin and clopidogrel combined with early aggressive medical management was effective for the prevention of recurrent vascular events. Our results are consistent with those reported in the clinical alert by the National Institute of Neurological Disorders and Stroke (NINDS), which recently stopped additional trial enrollment in the SAMMPRIS trial because of a higher 30-day risk of stroke and death among participants randomized to the stenting arm than those in the intensive medical therapy arm alone.11 The 30-day risk of stroke or death in the intensive medical therapy arm of SAMMPRIS was only 5.8%—substantially lower than the estimated rate of 10.7% based on historical controls who received standard medical care. These results have important implications in the management of patients with symptomatic intracranial stenosis. Our early aggressive medical management protocol was modeled after the intensive medical therapy arm of SAMMPRIS with the exception that our cohort was continued on dual antiplatelet therapy (aspirin 81 mg and clopidogrel 75 mg daily) beyond 3 months. We chose this dual antiplatelet regimen for several reasons: first, the WASID trial revealed that ischemic cerebrovascular events as opposed to hemorrhagic cerebrovascular events made up the majority of recurrent vascular events; second, in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, 77% of the cohort (n 5 12,153) were ‘‘symptomatic’’ patients (with documented coronary disease, cerebrovascular disease, or peripheral arterial disease) and those randomized to dual clopidogrel plus aspirin therapy had a significantly lower rate of MI, stroke, or cardiovascular death compared to aspirin monotherapy (6.9% v 7.9%; relative risk 0.88; 95% CI 0.77-0.998; P 5 .046) with no significant increase in severe bleeding among ‘‘symptomatic’’ patients (1.6% v 1.4%; P 5 .39) and no increased risk of cardiovascular death or all-cause mortality12; third, while the Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH) trial found that dual antiplatelet therapy was of no benefit when compared with clopidogrel monotherapy among patients with stroke or transient ischemic attack and associated with a small but significant increase in the risk of life-threatening bleeding (absolute risk increase of 1.3% over 18 months of follow-up),13 only one-third of MATCH trial patients had large vessel atherosclerosis as their mechanism of stroke, and of these, only 5% had a history of MI, much lower than previously described for this population.14 We agree with others who have questioned whether the MATCH results can be
extrapolated to patients with ischemic stroke secondary to large vessel atherosclerosis.14 Therefore, we recommend that these patients remain on long-term dual antiplatelet therapy with low-dose aspirin and clopidogrel unless they have an increased risk of bleeding (severe hepatic insufficiency, current peptic ulceration, history of systemic bleeding, or other history of coagulopathy). Another important implication of our study and the preliminary results of the SAMMPRIS trial relates to the optimal time when patients should be considered for stenting. While data from the WASID study suggest that antithrombotic ‘‘failure’’ at the qualifying event was not a predictor of recurrent stroke or vascular death, our results and those of the SAMMPRIS trial would suggest that intracranial stenting should be considered only after patients fail early aggressive medical management. Given that our current study reveals that high levels of risk factor targets can be achieved outside of a clinical trial setting, this approach may also be more cost effective given the high hospitalization charges among patients who undergo primary angioplasty or angioplasty-stenting when compared with ischemic stroke patients who do not undergo this procedure.15 Limitations of our study include the small sample size and relatively short follow-up. We were unable to include a control group treated with usual medical treatment because of the small sample size. While the patients were prospectively identified, data collection was obtained retrospectively. In addition, our study identified no patients who failed early aggressive medical management or had hypoperfusion as the primary mechanism of stroke in the territory, subgroups which may benefit from primary angioplasty or angioplasty-stenting.
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