© Springer International Publishing Switzerland 2016
Bruce Ovbiagele (ed.)Ischemic Stroke Therapeutics10.1007/978-3-319-17750-2_99. Traditional Stroke Risk Factor Treatment
(1)
Department of Neurology, Medical University of South Carolina, 96 Jonathan Lucas St, Suite 301 CSB—MSC 606, Charleston, SC 29425, USA
(2)
Medical University of South Carolina, Charleston, SC, USA
Keywords
AtherosclerosisRisk factorsDyslipidemiaHypertensionDiabetesLifestyleSmokingDietExerciseIntroduction
The greatest opportunity for decreased stroke incidence and mortality is through stroke prevention [1]. While the focus for every patient should be on the primary prevention of stroke, for many patients the need for true risk factor modification doesn’t become obvious until their first stroke has already occurred. For these patients, secondary prevention of stroke is crucial—the underlying pathophysiological mechanisms to which they are susceptible are already in progress, and now clearly manifesting clinically. However, despite studies suggesting that stroke can be prevented in 50–80 % of patients, this promising opportunity to reduce the burden of stroke is not broadly being realized [1]. Use of evidence-based therapies for the prevention of ischemic stroke in patients receiving conventional care remains inadequate, despite the available data and the current national guidelines that support their use [2]. A comprehensive discussion of this issue can be found in the sections detailing stroke systems of care.
The importance of early diagnosis and aggressive initiation of secondary prevention strategies for patients with acute ischemic cerebrovascular syndromes [3] is reinforced by community-based data that confirm a much higher early risk of subsequent stroke than was previously appreciated in patients with transient ischemic attacks (TIAs) or minor stroke [4]. The initiation of proven secondary prevention strategies is most effective when implemented early (before disabling stroke occurs), monitored frequently, and maintained long term after an index cerebrovascular event [5, 6]. As such, secondary prevention must start when the patient is admitted for stroke work-up and must be adapted to the individual’s needs. Fortunately, longitudinal epidemiologic studies have identified several modifiable stroke risk factors including hypertension, cardiac disease, diabetes mellitus, hyperlipidemia, cigarette smoking, alcohol abuse, physical inactivity, carotid stenosis, and prior stroke or transient ischemic attack [7].
Large Artery Atherosclerotic Disease—Which Patients Need Revascularization?
During work-up following ischemic stroke, it is common to find atherosclerotic plaque buildup in the extracranial carotid arteries. For these patients it is not always clear what, if any, intervention should be performed on the newly discovered stenosis and when it should be performed. For most patients with symptomatic extracranial high-grade carotid stenosis, there is a clear benefit to carotid endarterectomy (CEA) over carotid stenting (CS). However, the decision of whether or not to intervene rests on the answers to the following questions: (1) Does the stroke represent symptomatic stenosis, that is, was the stroke likely caused by the stenosis? (2) How severe is the stenosis? And (3) what are the patient’s other comorbidities and reasons for stenosis?.
Typically the answers to questions one and two are very much related. To make these assessments, one must consider the patient’s diagnostic images. Co-existing acute infarcts in other vascular territories should deflect blame from the stenotic vessel and refocus attentions towards more central or cardiogenic etiologies such as atrial fibrillation. However, even in these instances, a classic border zone appearance of infarcts on the corresponding side of the stenosis should still raise the question of a symptomatic stenosis in addition to possible cardiogenic process.
Once carotid stenosis is established as the causative mechanism, treatment may be guided by the principles discussed in the chapter on large artery atherosclerosis. If not causative and no other sources of stroke are identified, the risk factor modification discussed below should be implemented.
Lipid Modification
The need for adequate control of serum lipid levels for secondary prevention of stroke in patients with heterogeneous causes of stroke or TIA was illustrated by the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study [8]. SPARCL randomized 4,731 patients with ischemic or hemorrhagic stroke and no history to heart disease to atorvastatin 80 mg vs. placebo. During a median follow-up of almost 5 years, 11.2 % of patients receiving atorvastatin and 13.1 % receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 %, NNT = 45; adjusted hazard ratio, 0.84; 95 % confidence interval, 0.71–0.99; P = 0.03; unadjusted P = 0.05). SPARCL also showed that aggressively lowering low density lipoprotein (LDL) levels to <70 resulting in a 28 % reduction of subsequent ischemic stroke. For those patients who were able to achieve a reduction of 50 % from their baseline LDL, a 35 % decrease in the rate of stroke was seen. For this reason, the current AHA/ASA Secondary prevention of strokeguidelines recommend the use of high-dose statin medications for stroke patients following stroke thought to be due to atherosclerosis. For those thought to be due to a different etiology, moderate dose statins are recommended [1]. There is insufficient evidence to recommend the use of fibrates or niacin for secondary stroke prevention; however, in patients unable to tolerate statins, these medications may present a reasonable therapeutic option. There is some suggestion from the SPARCL and other trials that the use of statins may increase the risk of intracranial hemorrhage, and as such, some experts avoid use of statins in patients with ICH without known atherosclerotic cardiovascular disease.
Statins, however, have been shown to convey a multitude of beneficial effects beyond just lowering cholesterol which many feel outweigh any additional ICH risk that they may convey. These effects include improved endothelial function through antioxidant activity [9], plaque stabilization through reduction in inflammation and metalloproteinase activity [10], and inhibition of platelet deposition and thrombus formation on damaged vessel walls [11].
Discussion of Case Vignette 1
Key features of this case are the patient’s history of insulin-dependent diabetes, prior myocardial infarction, elevated LDL cholesterol and low HDL cholesterol levels. Based upon the history of coronary heart disease (CHD) and diabetes, the patient has established symptomatic atherosclerotic cardiovascular disease and a coronary heart disease risk equivalent (diabetes), regardless of whether his underlying stroke mechanism is determined to be atherosclerotic in nature. As such, we would recommend the use of high-dose statin therapy, typically atorvastatin 80 mg, which was used in the SPARCL trial, or Rosuvastatin 20 mg daily (another high-dose statin regimen). Aiming for an LDL cholesterol level <70 mg/dL may be appropriate based on a post hoc analysis of the SPARCL trial showing that recent stroke and TIA patients with an average LDL cholesterol of <70 mg/dL had significantly lower recurrent vascular events than those with LDL cholesterol levels >100 mg/dL [1]. If the patient is unable to tolerate the 80 mg dose, down titration to a lower dose (e.g., 40 mg of atorvastatin daily) with or without the addition of a non-statin lipid modifier agent (ezetimibe 10 mg daily). Low HDL cholesterol levels are associated with a higher risk of stroke, and boosting HDL cholesterol levels above 40 mg/dL in men has been recommended as a secondary lipid therapeutic target (after LDL cholesterol) in patients at high vascular risk. So far, HDL-boosting medications have either been ineffective or possibly harmful, so the main recommendation at this time (based on the best available evidence) for raising HDL cholesterol levels is advising the patient to engage in regular exercise accompanied by weight loss [1]. Additional efforts should be made to identify and mitigate other potential vascular risk factors in this patient, such as atrial fibrillation.
Blood Pressure Lowering
Hypertension is one of the most important risk factors for stroke, with the risk of first stroke increasing directly with blood pressure. But does this play as important a role in secondary stroke prevention, and if so, what are the best agents to use?
The Poststroke Antihypertensive Treatment Trial (PATS) and Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial proved the importance of blood pressure reduction in secondary stroke prevention, but also suggested that certain medication classes, namely diuretics and ACE inhibitors, may play a greater role in this fight than other drug classes. Many providers may mentally classify ACE inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) as being similar classes of drugs, switching a patient from an ACE-I to an ARB in cases of drug-related cough for example. However, for secondary stroke prevention these medication classes are far from equivalent. While ACE-I have been shown to be effective in not only lowering blood pressure but also reducing the incidence of secondary stroke, the Morbidity and Mortality after Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) [12] and the Prevention Regimen for Effective Avoiding Secondary Strokes (PRoFESS) [13] studies clearly illustrated that ARBs do not appear to confer additional benefit for stroke prevention beyond their blood pressure lowering properties when used as a secondary prevention mechanism for the prevention of stroke. In the PRoFESS trial, patients were randomized to the use of telmisartan 80 mg daily vs. placebo within an average of 15 days following stroke. After a mean follow-up of 2.5 years, no additional reduction in the rate of stroke, cardiovascular event, or diabetes was seen. Thus, it is not merely blood pressure lowering but the mechanism by which such lowering is attained that is important.
The degree of blood pressure control necessary for optimal secondary stroke prevention remains unclear, but current guidelines [14] suggest that the goal should be systolic blood pressure (SBP) <140 mmHg and diastolic blood pressure <90 mmHg. This has been illustrated by studies comparing targets of SBP <120 mmHg and SBP <140 mmHg, which showed no reduction in rate of stroke for those randomized to stricter blood pressure control [15]. The Secondary Prevention of Small Subcortical Strokes (SPS3) trial for the prevention of lacunar strokes randomized patients following recent lacunar or small vessel strokes to two blood pressure targets, <150 systolic blood pressure (SBP) or <130 SBP. Though there was an overall reduction in the number of strokes and cardiovascular events seen in patients assigned to SBP <130 mmHg group, there was no significant difference seen in the rate of recurrent stroke or other cardiovascular events between the two groups [16].
Glycemic Control
Insulin resistance and progressive destruction of insulin-secreting beta-islet cells of the pancreas are hallmarks of diabetes mellitus, which is defined as having a hemoglobin A1c of ≥6.5 %. Prediabetes, defined as impaired glucose tolerance, impaired fasting glucose, and moderate elevations in hemoglobin A1c (HgbA1c 5.7–6.4 %), is its precursor. Diabetes is highly prevalent in the US population and as many as 8 % of ischemic strokes may be directly attributable to poorly controlled diabetes [17]. By some estimates over 77 % of patients who have had a stroke are either prediabetic or diabetic [18], and the results of the Cardiovascular Health Study have implicated diabetes in causing as much as a 60 % increased risk of recurrent ischemic stroke [19].
A lack of studies specifically targeting diabetes control in stroke secondary prevention limits the ability to discuss the efficacy of interventions in this population; however information can be extrapolated from studies in non-stroke populations. There is no convincing evidence that intensive control of impaired glucose intolerance alters the incidence of larger vessel (so-called macrovascular) events. However, both lifestyle interventions and the use of metformin may prevent progression from a prediabetic state to frank diabetes mellitus, by 58 and 31 % respectively according to the Diabetes Prevention Program Trial [20]. The avoidance of progression to diabetes or reduced duration as a diabetic may have microvascular implications over time by limiting its role in the development of lipohyalinosis.
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