Lipid Management & Smoking Cessation

Lipid Management

High cholesterol is a well-known risk factor for the development of ischemic stroke. Concern related to the association between extremely low levels of cholesterol and increased risk of intracerebral hemorrhage (ICH), however, has resulted in hesitancy by some practitioners to prescribe statins to individuals at risk for stroke. The mechanism by which elevated levels of cholesterol may increase ICH risk is not fully understood; however, ischemic strokes resulting from atherosclerosis have been associated more consistently with higher levels of total cholesterol (TC) and LDL cholesterol (LDL-C). As a result, LDL-C is the lipid subfraction that is the target of treatment for vascular event prevention.

Numerous studies have investigated the effects of lipid lowering on risk of incident stroke (Table). A meta-analysis in 2010 of 26 trials included individuals with and without prior stroke and found a significant 21% reduction in ischemic stroke risk for every 39 mg/dL (1 mmol/L) reduction in LDL-C (relative risk [RR], 0.79; 95% CI 0.74 to 0.85). Conversely, there was a nonsignificant 12% increase in ICH risk for every 39 mg/dL (1 mmol/L) reduction in LDL-C (RR, 1.12; 95% CI 0.93 to 1.35).¹

Among individuals with prior stroke, 2 major trials focused specifically on lipid lowering therapy. In a trial in 4,731 participants with recent transient ischemic attack (TIA) thought to be atherosclerotic in origin, stroke, or ICH and without a history of coronary artery disease, high-dose atorvastatin (80 mg/ day) significantly lowered the incidence of fatal and nonfatal stroke compared with placebo, with 11.2 vs 13.1% events per year (1.9% 5-year absolute risk reduction [ARR]; HR, 0.84; 95% CI 0.71 to 0.99; P=.03).² A second trial focused on LDL treatment targets in 2,860 participants with recent ischemic stroke or TIA and atherosclerosis, comparing low (<70 mg/ dL) vs high (90-110 mg/dL) target LDL-C using open-label lipid lowering drugs (eg, any statin, ezetimibe, or both). The low LDL-C target was associated with significantly fewer major vascular events, the majority of which were ischemic strokes, when compared with the higher target, with 8.5% vs 10.9% events, respectively (adjusted HR, 0.78; 95% CI 0.61-0.98; P=.04).³

Both trials also evaluated the risk of ICH as a result of LDL-C lowering. Although there was a significant increase in ICH in those treated with atorvastatin vs placebo (HR, 1.68; 95% CI 1.08 to 2.55), subsequent analysis found ICH was strongly associated with stage II hypertension, prior ICH, and age. There was also no relationship between low LDL-C levels and risk of ICH, either at baseline or after treatment with statin.⁴ Along those lines, there was no significant difference in ICH between patients with low target LDL-C vs high target LDL-C. More recently, a Danish population-based study of more than 55,000 individuals found that statins did not increase the risk of ICH in those with a prior history of either ischemic stroke or ICH.⁵ Considering the high risk of recurrent stroke in those with stroke due to atherosclerosis, the benefit of lipid-lowering treatment greatly outweighs any perceived ICH risk.

Numerous lipid-modifying therapies exist, including high and low potency statins, ezetimibe, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, eicosapentaenoic acid ethyl ester, gemfibrozil, and niacin. Here we focus on lipid management with statins, ezetimibe, and PCSK9 inhibitors.

Specific Lipid-Lowering Agents and Mechanisms of Action

Statins lower serum cholesterol by inhibiting hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase, resulting in lowering of serum cholesterol; however, statins lead to a decreased risk of stroke via numerous mechanisms that go beyond lowering of cholesterol. In addition to their lipid-dependent effect, statins have also been shown to improve endothelial function, decrease inflammatory and oxidative stress, and modulate thrombogenesis. The effect of statins on endothelial function is thought to be related to the upregulation of endothelial nitric oxide synthase, which may mediate vasodilation and reduce vascular smooth muscle cell proliferation. By reducing the production of thromboxane A2 in platelet and erythrocyte membranes, statins act to reduce thrombogenesis. Damage resulting from inflammation and oxidative stress is mitigated through inhibition of inflammatory cell recruitment, adhesion, and migration as well as the reduction of reactive oxygen species by angiotensin III.⁶ These added benefits, or pleiotropic effects, likely provide the added protection against stroke that makes statins the first-line choice for LDL lowering in people who had a stroke. Commonly used statins are available in generic form and inexpensive, relative to other lipid-lowering medications.

Ezetimibe acts to lower cholesterol by inhibiting its absorption at the brush border of the jejunum,⁷ and has been shown to decrease LDL-C by roughly 10% to 18% alone, with an additional 25% lowering of LDL-C when used in combination with statins.⁸ A subanalysis of a clinical trial of ezetimibe demonstrated lower risk of ischemic stroke with the addition of ezetimibe to a statin compared with statin alone in people who had previous acute coronary syndrome (Table).⁹ Ezetimibe is also now generic and relatively inexpensive.

PCSK9 is a proprotein that regulates the degradation of the LDL receptor in response to cellular concentrations of cholesterol. PCSK9 inhibition increases the number of LDL receptors on liver cell surfaces, increasing the clearance of LDL-C from the circulation. Inherited variants in the PCSK9 gene cause a loss of function that results in very low plasma concentrations of LDL-C and cardiovascular events,¹⁰ which led to the development of PCSK9 inhibitors as a therapeutic approach to lowering LDL. PCSK9 inhibitors have been shown to reduce LDL-C levels by 50% to 60% and, when added to a statin in people with atherosclerotic disease and elevated LDL-C, lower the risk of cardiovascular events.^11,12 Another study demonstrated that the addition of a PCSK9 inhibitor to statin therapy in people with previous acute coronary syndrome (ACS) and elevated cholesterol resulted in a lower risk of recurrent ischemic cardiovascular events, including ischemic stroke, when compared to the use of statin monotherapy (Table).¹³ Despite being highly-effective, the use of PCSK9 inhibitors has been limited due to high cost (average retail cost over $450/month).

Lifestyle Modification

Adherence to lifestyle modifications also contributes to lowering of LDL-C. Studies have shown that reduction of caloric intake by 20% to 25% for at least 3 months results in lower LDL-C and triglycerides, in addition to positive effects on both blood pressure and glucose levels.¹⁴ Current guidelines recommend the adoption of a Mediterranean-type diet for reduction of vascular risk factors.¹⁵

Exercise training has also been shown to improve lipid profiles in persons who have had a stroke.¹⁴ The American Heart Association (AHA) recommends moderate to vigorous physical activity, defined as activity that increases the heart rate for at least 150 minutes per week.¹⁶

Practice Guidelines

Given the strong evidence supporting LDL reduction for stroke prevention, the most recent AHA stroke prevention guidelines recommend a target LDL-C of less than 70 mg/ dL in people who have had ischemic stroke or TIA and atherosclerotic disease to reduce the risk of major cardiovascular events (Figure).¹⁵ Atherosclerotic disease can be present in either intra- or extracranial arteries, the aortic arch, or coronary arteries to meet consideration for this target. This can be achieved with a statin and ezetimibe, if needed. Ezetimibe should be added to the maximum tolerated statin dose if additional lipid lowering is required. For patients who are unable to achieve this goal despite these 2 medications, the use of PCSK9 inhibitor therapy is a reasonable adjunct to therapy to prevent further cardiovascular events.

For efficient achievement of an LDL level less than 70 mg/ dL goal, a lipid panel should be repeated approximately 1 month after starting or adjusting lipid-lowering treatment and medication titrated as needed. Once on target, a repeat lipid panel is only needed once a year to assess adherence. If, however, an individual has a significant change in medication use (eg, decreases dose or stops medication), a lipid panel should be checked. The lipid panel can be performed with or without fasting, but if nonfasting triglycerides are above 400 mg/dL, a lipid panel with fasting should be done.¹⁵

Hypertriglyceridemia

Similar to the atherogenic effects of LDL, triglyceride-rich lipoproteins (very-low-density lipoprotein [VLDL] and chylomicrons) have been shown to increase development of atherosclerosis and contribute to cardiovascular disease and stroke risk. Although treatment with niacin and fibrates in combination with statin therapy may lower triglycerides, it has not demonstrated a significant reduction in cardiovascular events. However, the purified omega-3 fatty acid, icosapent ethyl (IPE), has shown benefit for prevention of vascular events. In a clinical trial in 8,179 participants with atherosclerotic cardiovascular disease, 70% of whom had a history of ischemic stroke or TIA, treatment with IPE 4 g/day in 2 divided doses plus statin vs statin therapy alone reduced fatal or nonfatal stroke by 28% (2.4% vs 3.3%; HR, 0.72 [95% CI 0.55-0.93]; P=.01).¹⁷ The current AHA stroke prevention guidelines state it is reasonable to add IPE to reduce the risk of recurrent stroke in individuals with moderate hypertriglyceridemia (fasting triglycerides of 135-499 mg/dL) already on moderate- or high-intensity statin therapy. Of note, however, there was a significant increase in atrial fibrillation with IPE (5.3% vs 3.9%, P=.003) and the trial excluded those with a glycated hemoglobin level greater than 10.0%, severe heart failure, or history of pancreatitis. Omega-3 fatty acids also appear to have an antiplatelet effect, which may be a concern in those being treated with antithrombotic medications. Studies of prescription omega-3 fatty acids, however, have not shown clinically significant increases in bleeding events.¹⁸

The benefit of vascular event reduction appears to be limited to IPE, as subsequent studies with other forms of purified omega-3 compounds have not shown any benefit for prevention of vascular events.¹⁹ Unfortunately, the cost of IPE (average retail price over $300 a month) also limits its use and nonprescription omega-3 compounds may be chemically unstable and are not advised.²⁰ Prior to starting treatment for hypertriglyceridemia, reversible causes of hypertriglyceridemia, including medication effect (eg, exogenous estrogen or some diuretics) or some medical conditions (eg, hypothyroidism or excessive alcohol use) should be corrected if possible.

Tobacco Use and Stroke

Tobacco use remains a major issue both in the US and worldwide and is the leading cause of preventable disease and death in the US. According to the Centers for Disease Control and Prevention (CDC), it is estimated that nearly 40 million adults in the US smoke cigarettes.²¹ Numerous studies worldwide have demonstrated an association between cigarette smoking and stroke, and some studies have further elucidated a dose-dependent effect with regard to cigarette smoking, with the risk of stroke increasing as the number of cigarettes smoked increased.^22,23 A 2019 meta-analysis of 14 studies found a 12% increase in risk of stroke for every 5 cigarettes smoked per day (95% CI 0.01 to 0.02; P<.001).²⁴ Current cigarette smokers have at least a two- to fourfold increase in stroke risk compared with nonsmokers or former smokers who quit more than 10 years earlier.²² These findings suggest that quitting smoking is ideal, but if stopping is not possible, reducing the number of cigarettes might provide some benefit.

Smoking causes stroke by promotion of a thrombotic state as well as arterial vasoconstriction, which decreases cerebral blood flow. Smoking cessation improves both of these.²⁵ A caveat to this is that, among people treated with antiplatelet therapy with clopidogrel, studies have shown that smoking potentiates the antithrombotic effect of clopidogrel through its induction of CYP1A2 and increased conversion of clopidogrel to its active metabolite.^26,27 Another mechanism for injury from cigarette smoke is induction of vascular inflammation and oxidative stress, promoting the development of atherosclerosis. Through the creation of matrix metalloproteinases, cigarette smoke can affect vascular remodeling and plaque stability, potentially contributing to plaque erosion or rupture, both of which play a role in the development of stroke.²⁸

Passive Smoking

In addition to active smoking, passive smoking has also been shown to increase stroke risk, with a 45% increase in stroke risk seen in individuals exposed to secondhand smoke compared with those with no exposure (OR, 1.45; 95% CI 1.0 to 2.11; P<0.05).^24,29 Passive smoking contributes to stroke risk through many mechanisms, including the development of carotid atherosclerosis, increased levels of homocysteine and fibrinogen, and elevations in LDL. In addition, smoking is related to several underlying risk factors for stroke, including hypertension, diabetes, and elevated resting heart rate.²⁴

Methods for Smoking Cessation

Although a large percentage of smokers desire to quit (73% in 1 study), fewer than 5% succeed without assistance.³⁰ The importance of smoking cessation is further underscored by the fact that in those who quit smoking, stroke risk decreases to the level of nonsmokers by 5 years.^23,31

Many studies have evaluated the efficacy of different cessation methods, with completion of a structured smoking cessation program correlating with the greatest rate of success. A meta-analysis of 633 studies that evaluated different cessation methods showed that physician counseling-based programs were less effective than instruction-based programs (eg, group withdrawal clinics, 5-day plans, or educational methods) and aversive techniques (ie, pairing the stimulus with a noxious response). Drug-based programs that incorporated the use of nicotine replacement therapy, lozenges, and naturally derived products were slightly less effective than both instruction-based programs and aversive techniques; however, this meta-analysis was published prior to the use of varenicline or bupropion for smoking cessation. Overall, the data from these analyses supports the idea that incorporation of social norms, enhancement of self-esteem, and environmental contingencies contribute to effectiveness of instruction-based cessation programs.³² Intensive counseling beginning during the hospital stay with continued support for at least 1 month after discharge is effective for smoking cessation, regardless of the reason for hospital admission.³³ The combination of behavioral intervention and pharmacotherapy (eg, with nicotine replacement therapy, varenicline, or bupropion) is more effective than less intensive counseling alone.³⁴

Electronic Cigarettes or Vaping

The use of electronic cigarettes has become a popular alternative to traditional cigarette use as well as an aid in smoking cessation for many individuals. Marketing of these products creates the perception that electronic cigarettes are safer than traditional cigarettes; however, data suggests that there may be serious health risks associated with their use. A recent study of 16,855 participants, including electronic cigarette users, tobacco users, dual users of electronic cigarettes and tobacco, and former tobacco users, demonstrated an increased risk of stroke in dual users as well as former tobacco users with and without current use of electronic cigarettes.³⁵

Practice Guidelines

The current AHA stroke prevention guidelines recommend that people with stroke or TIA who continue to smoke tobacco should be advised to stop smoking or reduce their daily smoking if they are unable to quit. The guidelines also recommend that these individuals avoid passive exposure to tobacco smoke. Lastly, counseling with or without drug therapy is recommended to assist in smoking cessation.¹⁵ Most US State health departments offer free smoking cessation programs, in some cases even including free smoking cessation medications. Healthcare providers should be aware of the resources available and can access more information at the CDC website: https://www.cdc.gov/tobacco/stateandcommunity/tobacco-control/index.htm.