Discussion

Relative and Cumulative Effects of Lipid and Blood Pressure Control
in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trial


Cited from: Ameranco P et al Stroke. 2009;40:2486-2492

The SPARCL trial randomized 4731 patients with recent stroke or TIA and no known coronary heart disease to treatment with atorvastatin 80 mg per day or placebo, and found a significant reduction in stroke and major cardiovascular events (stroke, cardiac death, nonfatal myocardial infarction, or resuscitated cardiac arrest).1 A post hoc analysis found that the subjects with more than a 50% reduction in LDL-C from baseline had greater benefit than in those for whom there was no change or an increase in LDL-C.2. Baseline values of HDL-C and triglycerides were predictive of outcome stroke and major cardiovascular events.3 Blood pressure reduction after stroke has also been shown to reduce the risk of both recurrent stroke and major cardiovascular events.4 In this exploratory analysis of the SPARCL data, we assessed the relative contributions of reductions in LDL-C and triglycerides, levels of HDL-C, and BP control.

Background and Purpose

The relative contributions of on-treatment low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), triglycerides, and blood pressure (BP) control on the risk of recurrent stroke or major cardiovascular events in patients with stroke is not well defined.

Methods

We randomized 4731 patients with recent stroke or transient ischemic attack and no known coronary heart disease to atorvastatin 80 mg per day or placebo.

Results

After 4.9 years, at each level of LDL-C reduction, subjects with HDL-C value above the median or systolic BP below the median had greater reductions in stroke and major cardiovascular events and those with a reduction in triglycerides above the median or diastolic BP below the median showed similar trends. There were no statistical interactions between on-treatment LDL-C, HDL-C, triglycerides, and BP values. In a further exploratory analysis, optimal control was defined as LDL-C
70 mg per deciliter, HDL-C 50 mg per deciliter, triglycerides
150 mg per deciliter, and SBP/DBP
120/80 mm Hg. The risk of stroke decreased with as the level of control increased (hazard ratio [95% confidence interval] 0.98 [0.76 to 1.27], 0.78 [0.61 to 0.99], 0.62 [0.46 to 0.84], and 0.35 [0.13 to 0.96]) for those achieving optimal control of 1, 2, 3, or 4 factors as compared to none, respectively. Results were similar for major cardiovascular events.

Conclusions

We found a cumulative effect of achieving optimal levels of LDL-C, HDL-C, triglycerides, and BP on the risk of recurrent stroke and major cardiovascular events. The protective effect of having a higher HDL-C was maintained at low levels of LDL-C.

In this exploratory analysis, we found that SPARCL subjects with a 1-month reduction in LDL-C above the median had
greater reductions in stroke and major cardiovascular events than those with smaller LDL-C reductions. At each level of
LDL-C reduction, subjects with a 1-month HDL-C value above the median had greater reductions in stroke and major
cardiovascular events. There was no additive effect of above the median triglyceride lowering compared with below the
median lowering for each strata of LDL-C reduction. At each level of LDL-C reduction, there was a reduction in stroke and
major cardiovascular events for subjects with a 6-month systolic BP below the median compared with those above the median, but no significant effect of diastolic BP. In a further exploratory analysis, we also found a cumulative effect of lowering LDL-C, triglycerides, and BP and of higher HDL-C in reducing the risk of stroke and major cardiovascular events.
The observation that those having a 1-month HDL-C above the median (47 mg per deciliter) and a 6-month systolic BP
below the median (
138 mm Hg) significantly reduced the risk of stroke and major cardiovascular events, without level of LDL-C reduction suggests that the benefit of modifying these risk factors is additive rather than multiplicative.

This has also been observed for HDL-C in the Treating to New Target (TNT) trial,6 and for BP in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).7 As observed in the TNT trial in patients with stable coronary heart disease,6 we found that the protective effect of HDL-C above 47 mg per deciliter seems maintained at low levels of LDL-C in patients with cerebrovascular disease (Table 2). In ASCOT, a potential synergistic effect of LDL-C and BP was found for coronary heart disease reduction (P0.025 for heterogeneity), but LDL-C and BP-lowering therapies had an additive effect for stroke risk reduction with no significant interaction.7 Our findings confirm that BP is a major predictor of stroke and major cardiovascular risks after a stroke or a TIA, but suggest that HDL-C is also important. This observation suggests that there may be a role for HDL-modifying agents in secondary stroke prevention. Although there was a trend, median triglyceride lowering of more than 15% from baseline had no additive effect in subjects who had a median LDL-C reduction more than 16% from baseline. Triglycerides
150 mg per deciliter was independently associated with lower risk of coronary heart disease events beyond the effect of having a low LDL-C in patients after acute coronary syndrome in the Pravastatin or Atorvastatin Evaluation and Infection Therapy- Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial.8 Because the median reduction in triglycerides levels in SPARCL was only 15%, it is possible that agents that lower triglycerides further might have a greater impact in the reduction of recurrent stroke and major cardiovascular events.9 The observation that there was an incremental impact of achieving optimal levels of 1, 2, 3, or 4 of these factors reinforces the need for developing strategies to optimize long-term compliance with secondary prevention interventions, such as with dedicated stroke prevention clinics.10–13 Our study was limited by its exploratory nature. The SPARCL trial was not designed and powered for these analyses. Therefore, these results should be interpreted as hypothesis generating and with appropriate caution.

View original article