K. Michael A. Welch

Effects of Intense Low-Density Lipoprotein Cholesterol Reduction in Patients With Stroke or Transient Ischemic Attack The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

Background and Purpose— The intention-to-treat analysis of data from the placebo-controlled Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found 80 mg atorvastatin per day reduced the risk of stroke and major coronary events in patients with recent stroke or transient ischemic attack. This benefit was present despite only a 78% net difference in adherence to randomized treatment over the course of the trial. In this exploratory analysis, our aim was to evaluate the benefit and risks associated with achieving a ≥50% low-density lipoprotein cholesterol (LDL-C) reduction from baseline. Methods— This post hoc analysis was based on 55 045 LDL-C measurements among the 4731 patients enrolled in SPARCL (average, 11.6 measurements per patient) during a mean follow-up of 4.9 years. At each postrandomization LDL-C assessment, percent change in LDL-C from baseline for each patient was classified as no change or increase from baseline (32.7% of measurements), <50% LDL-C reduction (39.4%), or ≥50% reduction (27.9%). Results— Compared with no change or an increase in LDL-C, analysis of time-varying LDL-C change showed that patients with ≥50% LDL-C reduction had a 31% reduction in stroke risk (hazard ratio, 0.69, 95% CI, 0.55 to 0.87, P=0.0016), a 33% reduction in ischemic stroke (P=0.0018), no statistically significant increase in hemorrhagic stroke (P=0.8864), and a 37% reduction in major coronary events (P=0.0323). There was no increase in the incidence of myalgia or rhabdomyolysis. Persistent liver enzyme elevations were more frequent in the group with ≥50% LDL-C reduction. Conclusions— As compared with having no change or an increase in LDL-C, achieving a ≥50% lowering was associated with a greater reduction in the risk of stroke and major coronary events with no increase in brain hemorrhages.

Atorvastatin Reduces the Risk of Cardiovascular Events in Patients With Carotid Atherosclerosis: A Secondary Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

Background and Purpose— The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found that treatment with atorvastatin 80 mg per day reduced the risk of stroke and cardiovascular events in patients with a recent transient ischemic attack (TIA) or stroke. We hypothesized this benefit would be greatest in the subgroup of patients with carotid stenosis. Methods— The SPARCL trial randomized patients with TIA or stroke within 1 to 6 months without known coronary heart disease (CHD) and low-density lipoprotein cholesterol 100 to 190 mg/dL to treatment with atorvastatin 80 mg per day or placebo. Investigators identified subjects as having carotid stenosis not requiring revascularization at the time of randomization. Of the total SPARCL population, 1007 were documented as having carotid stenosis at baseline, 3271 did not, and the status of 453 was unknown. Results— We found no heterogeneity in the treatment effect for the SPARCL primary (fatal and nonfatal stroke) and secondary end points between the group with and without carotid stenosis. The group with carotid artery stenosis had greater benefit when all cerebro- and cardiovascular events were combined. In the group with carotid artery stenosis, treatment with atorvastatin was associated with a 33% reduction in the risk of any stroke (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.47, 0.94; P=0.02), and a 43% reduction in risk of major coronary events (HR 0.57, 95% CI 0.32, 1.00; P=0.05). Later carotid revascularization was reduced by 56% (HR 0.44, 95% CI 0.24, 0.79; P=0.006) in the group randomized to atorvastatin. Conclusion— Consistent with the overall results of the SPARCL intention to treat population, intense lipid lowering with atorvastatin reduced the risk of cerebro- and cardiovascular events in patients with and without carotid stenosis. The carotid stenosis group may have greater benefit.

Relation between migraine and stroke

A complex bidirectional relation between migraine, mostly migraine with aura (MA), and ischaemic stroke is known. A cerebral infarction can occur during a MA, and MA is a risk factor for ischaemic stroke, particularly in young women. Conversely, cerebral ischaemia can induce MA. Both ischaemic stroke and MA might be consequences of many underlying vascular disorders. Despite the relation between migraine and stroke, migraine as a primary headache disorder is mostly benign.

Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial by Stroke Subtypes

Background and Purpose— The SPARCL trial showed that atorvastatin 80 mg/d reduces the risk of stroke and other cardiovascular events in patients with recent stroke or transient ischemic attack (TIA). We tested the hypothesis that the benefit of treatment varies according to index event stroke subtype. Methods— Subjects with stroke or TIA without known coronary heart disease were randomized to atorvastatin 80 mg/d or placebo. The SPARCL primary end point was fatal or nonfatal stroke. Secondary end points included major cardiovascular events (MCVE; stroke plus major coronary events). Cox regression models testing for an interaction with treatment assignment were used to explore potential differences in efficacy based on stroke subtype. Results— For subjects randomized to atorvastatin versus placebo, a primary end point occurred in 13.1% versus 18.6% of those classified as having large vessel disease (LVD, 15.8% of 4,731 participants), in 13.1% versus 15.5% of those with small vessel disease (SVD, 29.8%), in 11.2% versus 12.7% of those with ischemic stroke of unknown cause (21.5%), in 7.6% versus 8.8% of those with TIA (30.9%), and in 22.2% versus 8.3% of those with hemorrhagic stroke (HS, 2%) at baseline. There was no difference in the efficacy of treatment for either the primary end point (LVD hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49 to 1.02, TIA HR 0.81, CI 0.57 to 1.17, SVD HR 0.85, CI 0.64 to 1.12, unknown cause HR 0.87, CI 0.61 to 1.24, HS HR 3.24, CI 1.01 to 10.4; P for heterogeneity=0.421), or MCVEs (P for heterogeneity=0.360) based on subtype of the index event. As compared to subjects with LVD strokes, those with SVD had similar MCVE rates (19.2% versus 18.5% over the course of the trial), and similar overall reductions in stroke and MCVEs. Conclusions— Atorvastatin 80 mg/d is similarly efficacious in preventing strokes and other cardiovascular events, irrespective of baseline ischemic stroke subtype.

Ovarian steroids regulate neuropeptides in the trigeminal ganglion

Women are more than three times as likely as men to experience migraine headaches and temporomandibular joint pain, and painful episodes are often linked to the menstrual cycle. To understand how hormone levels may influence head and face pain, we assessed expression of pain-associated neuropeptides and estrogen receptor alpha (ERalpha) during the natural estrous cycle in mice. Gene expression was analyzed in the trigeminal ganglia of cycling female mice at proestrus, estrus and diestrus using RT-PCR. Peptide/protein expression in trigeminal neurons was analyzed using immunohistochemistry. ERalpha mRNA was present at all stages and highest at estrus. ERalpha protein was present in the cytoplasm of medium-sized and small trigeminal neurons. ERalpha immunoreactive neurons were most common at diestrus. CGRP and ANP mRNAs did not change across the estrous cycle, while expression of galanin and NPY mRNAs were strongly linked to the estrous cycle. Galanin mRNA levels peaked at proestrus, when expression was 8.7-fold higher than the diestrus levels. Galanin immunoreactivity also peaked at proestrus. At proestrus, 7.5% of trigeminal neurons contained galanin, while at estrus, 6.2% of trigeminal neurons contained galanin, and at diestrus, 4.9% of trigeminal neurons contained galanin. NPY mRNA peaked at estrus, when levels were 4.7-fold higher than at diestrus. Our findings suggest that estrogen receptors in trigeminal neurons modulate nociceptive responses through effects on galanin and NPY. Variations in neuropeptide content in trigeminal neurons across the natural estrous cycle may contribute to increases in painful episodes at particular phases of the menstrual cycle.

Relative Effects of Statin Therapy on Stroke and Cardiovascular Events in Men and Women. Secondary Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study

Background and Purpose— In SPARCL, treatment with atorvastatin 80 mg daily reduced stroke risk in patients with recent stroke or TIA and no known coronary heart disease by 16% versus placebo over 4.9 years of follow-up. The purpose of this secondary analysis was to determine whether men and women similarly benefited from randomization to statin treatment. Methods— The effect of sex on treatment-related reductions in stroke and other cardiovascular outcomes were analyzed with Cox regression modeling testing for sex by treatment interactions. Results— Women (n=1908) constituted 40% of the SPARCL study population. At baseline, men (n=2823) were younger (62.0±0.21versus 63.9±0.27 years), had lower systolic BPs (138.1±0.35 versus 139.5±0.47 mm Hg), higher diastolic BPs (82.2±0.20 versus 81.0±0.25 mm Hg), more frequently had a history of smoking (73% versus 38%), and had lower total cholesterol (207.0±0.54 versus 218.9±0.67 mg/dL) and LDL-C levels (132±0.45 versus 134±0.57 mg/dL) than women. Use of antithrombotics and antihypertensives were similar. After prespecified adjustment for region, entry event, time since event, and age, there were no sex by treatment interactions for the combined risk of nonfatal and fatal stroke (treatment Hazard Ratio, HR=0.84, 95% CI 0.68, 1.02 in men versus HR=0.84, 95% CI 0.63, 1.11 in women; treatment×sex interaction P=0.99), major cardiac events (HR=0.61, 95% CI 0.42, 0.87 in men versus HR=0.76, 95% CI 0.48, 1.21 in women; P=0.45), major cardiovascular events (HR=0.78, 95% CI 0.65, 0.93 in men versus HR=0.84, 95% CI 0.65, 1.07 in women; P=0.63), revascularization procedures (HR=0.50, 95% CI 0.37, 0.67 in men versus HR=0.76, 95% CI 0.46, 1.24 in women; P=0.17), or any CHD event (HR=0.54, 95% CI 0.41, 0.72 in men versus 0.67 95% CI 0.46, 0.98 in women; P=0.40). Conclusion— Stroke and other cardiovascular events are similarly reduced with atorvastatin 80 mg/d in men and women with recent stroke or TIA.

Risk of Stroke and Cardiovascular Events After Ischemic Stroke or Transient Ischemic Attack in Patients With Type 2 Diabetes or Metabolic Syndrome: Secondary Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

OBJECTIVE To perform a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which tested the effect of treatment with atorvastatin in reducing stroke in subjects with a recent stroke or transient ischemic attack, to explore the effects of treatment in subjects with type 2 diabetes mellitus or metabolic syndrome (MetS). METHODS The 4731 subjects enrolled in the SPARCL trial were classified as having type 2 diabetes mellitus at enrollment (n = 794), MetS retrospectively (n = 642), or neither diabetes nor MetS (n = 3295, the reference group) based on data collected at baseline. Cox regression models were used to determine whether the effect of treatment on the primary end point (combined risk of nonfatal and fatal stroke) and secondary end points (major coronary events, major cardiovascular events, any coronary heart disease event, and any revascularization procedure) varied based on the presence of type 2 diabetes mellitus or MetS. RESULTS Subjects with type 2 diabetes mellitus had increased risks of stroke (hazard ratio [HR] = 1.62; 95% confidence interval [CI], 1.33-1.98; P < .001), major cardiovascular events (HR = 1.66; 95% CI, 1.39-1.97; P < .001), and revascularization procedures (HR = 2.39; 95% CI, 1.78-3.19; P < .001) compared with the reference group. Subjects with MetS were not at increased risk for stroke (P = .78) or major cardiovascular events (P = .38) but more frequently had revascularization procedures (HR = 1.78; 95% CI, 1.26-2.5; P = .001). There were no treatment × subgroup interactions for the SPARCL primary end point (P = .47). CONCLUSIONS The SPARCL subjects with type 2 diabetes were at higher risk for recurrent stroke and cardiovascular events. This exploratory analysis found no difference in the effect of statin treatment in reducing these events in subjects with or without type 2 diabetes or MetS. Trial Registration clinicaltrials.gov Identifier: NCT00147602.

Coronary Heart Disease Risk in Patients With Stroke or Transient Ischemic Attack and No Known Coronary Heart Disease Findings From the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

Background and Purpose— Noncoronary forms of atherosclerosis (including transient ischemic attacks or stroke of carotid origin or >50% stenosis of the carotid artery) are associated with a 10-year vascular risk of >20% and are considered as a coronary heart disease (CHD) -risk equivalent from the standpoint of lipid management. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial included patients with stroke or transient ischemic attack and no known CHD regardless of the presence of carotid atherosclerosis. We evaluated the risk of developing clinically recognized CHD in SPARCL patients. Methods— A total of 4731 patients (mean age, 63 years) was randomized to 80 mg/day atorvastatin placebo. The rates of major coronary event, any CHD event, and any revascularization procedure were evaluated. Results— After 4.9 years of follow-up, the risks of a major coronary event and of any CHD end point in the placebo group were 5.1% and 8.6%, respectively. The rate of outcome of stroke decreased over time, whereas the major coronary event rate was stable. Relative to those having a large vessel-related stroke at baseline, those having a transient ischemic attack, hemorrhagic stroke, small vessel stroke, or a stroke of unknown cause had similar absolute rates for a first major coronary event and for any CHD event; transient ischemic attack, small vessel, and unknown cause groups had lower absolute revascularization procedure rates. Major coronary event, any CHD event, and any revascularization procedure rates were similarly reduced in all baseline stroke subtypes in the atorvastatin arm compared with placebo with no heterogeneity between groups. Conclusion— CHD risk can be substantially reduced by atorvastatin therapy in patients with recent stroke or transient ischemic attack regardless of stroke subtype.

Atherogenic dyslipidemia and residual cardiovascular risk in statin-treated patients

Background and Purpose— Treatment with statins reduces the rate of cardiovascular events in high-risk patients, but residual risk persists. At least part of that risk may be attributable to atherogenic dyslipidemia characterized by low high-density lipoprotein cholesterol (⩽40 mg/dL) and high triglycerides (triglycerides ≥150 mg/dL). Methods— We studied subjects with stroke or transient ischemic attack in the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM; n=19 100) and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL; n=4731) trials who were treated with a statin and who had high-density lipoprotein cholesterol and triglycerides measurements 3 months after randomization (n=10 498 and 2900, respectively). The primary outcome measure for this exploratory analysis was the occurrence of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). We also performed a time-varying analysis to account for all available high-density lipoprotein cholesterol and triglyceride measurements. Results— A total of 10% of subjects in PERFORM and 9% in SPARCL had atherogenic dyslipidemia after ≥3 months on start statin therapy. After a follow-up of 2.3 years (PERFORM) and 4.9 years (SPARCL), a major cardiovascular event occurred in 1123 and 485 patients in the 2 trials, respectively. The risk of major cardiovascular events was higher in subjects with versus those without atherogenic dyslipidemia in both PERFORM (hazard ratio, 1.36; 95% confidence interval, 1.14–1.63) and SPARCL (hazard ratio, 1.40; 95% confidence interval, 1.06–1.85). The association was attenuated after multivariable adjustment (hazard ratio, 1.23; 95% confidence interval, 1.03–1.48 in PERFORM and hazard ratio, 1.24; 95% confidence interval, 0.93–1.65 in SPARCL). Time-varying analysis confirmed these findings. Conclusions— The presence of atherogenic dyslipidemia was associated with higher residual cardiovascular risk in PERFORM and SPARCL subjects with stroke or transient ischemic attack receiving statin therapy. Specific therapeutic interventions should now be trialed to address this residual risk.

Effect of High-Dose Atorvastatin on Renal Function in Subjects With Stroke or Transient Ischemic Attack in the SPARCL Trial

Background and Purpose— Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins’ pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100–190 mg/dL). Methods— We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, <60 mL/min per 1.73 m2; n=3119) and without (eGFR, ≥60 mL/min per 1.73 m2; n=1600) chronic kidney disease overall and by glycemic status at baseline. Results— Mean baseline eGFR was similar between treatment groups (65.5±0.26 versus 65.6±0.26 mL/min per 1.73 m2 atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P=0.55). After 60 months, eGFR increased 3.46±0.33 mL/min per 1.73 m2 in those randomized to atorvastatin versus 1.42±0.34 mL/min per 1.73 m2 in those randomized to placebo (P<0.001) independent of baseline renal function. In the subgroup with diabetes mellitus at randomization, eGFR increased 1.12±0.92 mL/min per 1.73 m2 in the atorvastatin group and decreased 1.69±0.92 mL/min per 1.73 m2 in placebo group during a period of 60 months (P=0.016). Conclusions— This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00147602.