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Macrovascular Residual Risk THROUGH LANDMARK STUDY

19 December 2019
Treat Stroke to Target Study: Lower low-density lipoprotein cholesterol target after stroke reduces cardiovascular events

In patients with an ischaemic stroke or transient ischaemic attack (TIA) and evidence of atherosclerotic disease, lowering low-density lipoprotein cholesterol (LDL-C) levels to < 70 mg/dL (<1.8 mmol/L) reduces the risk of subsequent cardiovascular (CV) events compared with a higher target (90 to 110 mg/dL [2.3 to 2.8 mmol/L]).

Amarenco P, Kim JS, Labreuche J et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med 2019; DOI: 10.1056/NEJMoa1910355
Summary
Comments & References
STUDY SUMMARY
Objective:   To investigate target levels for LDL-C to reduce CV events after stroke.
Study design: Multicentre, randomized, parallel-group, event-driven trial conducted in France (61 centres) and South Korea (16 centres). Patients with an ischaemic stroke within the last 3 months or a TIA within the previous 15 days were randomized (1:1) to a target LDL-C <70 mg/dL (lower-target group) or 90 - 110 mg/dL (higher-target group).  LDL-C was measured 3 weeks after randomization, with adjustment of the statin dose and, if needed, addition of other lipid-lowering agents to attain the required LDL-C target. Patients were followed every 6 months thereafter.
Study population: The study included 2860 eligible patients (1430 assigned to each target group). The majority were male (67-68%), had a mean age of 66.4-67.0 years and a high prevalence of risk factors (64-67% had hypertension, 61-62% had dyslipidaemia, 51-56% had a smoking history and 22-23% had diabetes). Over half were not previously treated with a statin (mean baseline LDL-C 135-136 mg/dL).
Efficacy variables:

·       Primary endpoint: a composite of major CV events including ischaemic stroke, myocardial infarction (MI), new symptoms leading to urgent coronary or carotid revascularization, or death from CV causes.

·       Secondary endpoints: 1) MI or urgent coronary revascularization after the onset of new symptoms; 2) cerebral infarction or urgent revascularization of a carotid or cerebral artery after TIA; 3) cerebral infarction or TIA; 4) any revascularization of a coronary, cerebral, or peripheral artery (either urgent or elective); 4) CV death; 5) death from any cause; 6) cerebral infarction or intracranial haemorrhage (ICH); 7) ICH; 8) newly diagnosed diabetes; and 9) a composite of the primary end point or ICH.

All incident events that were components of these end points were adjudicated by a committee in which the members were unaware of trial-group assignment or LDL-C levels.

Methods: This was an event-driven trial. It was estimated that enrolment of 3786 patients would result in 385 primary endpoints and provide 80% power to detect a 25% lower relative risk of major CV events in the lower-target group vs. the higher-target group over 3 years of follow-up and with a 20% drop-out rate. The trial was stopped for administrative reasons after 277 endpoint events. The primary efficacy analysis was performed using a Cox proportional-hazards regression model including age, sex, index event (stroke or TIA), and the time since the index event as covariates. Missing values for covariates were handled using a multiple-imputation technique. Log-rank tests were used to analyse the secondary end points according to a hierarchical procedure to control for multiple comparisons.
Main results:

The median duration of follow-up was 3.5 years (interquartile range [IQR], 2.0 to 6.7) in the lower-target group and 3.6 years (IQR 2.0 to 6.7) in the higher-target group. Over this time, mean LDL-C levels were 65 mg/dL (1.7 mmol/L) in the lower-target group and 96 mg/dL (2.5 mmol/L) in the higher-target group.  In the lower-target group, 47.2% of patients had LDL-C levels >70 mg/dL, 44.7% had LDL-C levels between 50 mg/dL and 70 mg/dL, and the remainder had LDL-C levels <50 mg/dL. In the higher-target group, 48.5% had LDL-C levels <90 mg/dL, and 16.8% had LDL-C levels >110 mg/dL.

 

Overall, 65.9% of the lower-target group and 94.0% of the higher-target group received a statin, and 33.8% and 5.8%, respectively, received ezetimibe plus a statin. At a median of 2.7 years in the two groups, discontinuation rates were similar (30.3% and 28.5%, respectively). The percentage of time in the assigned therapeutic range was 52.8% in the lower-target group and 32.2% in the higher-target group; this was similar in patients recruited by French and Korean centres.

 

Results of the primary and secondary efficacy analyses are summarised below.  Patients in the lower LDL-C target group had a lower risk of subsequent major CV events (primary endpoint) than those assigned to the higher target group. Most of these events were cerebral infarctions or strokes of indeterminate origin. Hazard ratios for all secondary end points were generally in the same direction as the hazard ratio for the primary end point. While the number of ICH events was higher in the lower-target group than in the higher-target group, the 95% confidence interval (CI) for suggested that the between-group difference was not significant.

 

Table 1. Hazard ratios (95% CI) for primary and secondary endpoints

Endpoint

Lower target group                  (≤70 mg/dL)

(N=1430)

Higher target group (90-110 mg/dL) (N=1430)

Hazard ratio                  (95% CI)

p-value

 

No. (%) of events

 

 

Primary endpoint

121 (8.5)

156 (10.9)

0.78 (0.61–0.98)*

0.04

Secondary endpoints

 

 

 

 

 MI/coronary revascularization

20 (1.4)

31 (2.2)

0.64 (0.37–1.13)

0.12**

 Cerebral infarction/ revascularization

88 (6.2)

109 (7.6)

0.81 (0.61–1.07)

 

 Cerebral infarction/TIA

120 (8.4)

139 (9.7)

0.87 (0.68–1.11)

 

 Any revascularization

94 (6.6)

99 (6.9)

0.93 (0.70–1.24)

 

 CV death

22 (1.5)

22 (1.5)

0.69 (0.40–1.18)

 

 All-cause death

88 (6.2)

93 (6.5)

0.97 (0.73–1.30)

 

 Cerebral infarction/ICH

103 (7.2)

126 (8.8)

0.82 (0.63–1.07)

 

 ICH

18 (1.3)

13 (0.9)

1.38 (0.68–2.82)

 

 New-onset diabetes***

103 (7.2)

82 (5.7)

1.27 (0.95–1.70)

 

* Adjusted for covariates;

** p-values for additional secondary endpoints were not calculated as there was no significant between-group difference for the first endpoint on hierarchical testing;

*** new-onset diabetes was defined as at least two measures of fasting glucose ≥126 mg/dL (7.0 mmol/L) or HbA1c ≥6.5% at a follow-up visit. This classification was not adjudicated.    
Authors’ conclusion: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL-C level of <70 mg/dL had a lower risk of subsequent CV events than those who had a higher target range (90 - 110 mg/dL).

COMMENT

Current guidelines recommend intensive statin therapy for prevention of CV events following an ischaemic stroke or TIA,1 supported by results from the Stroke Prevention by Aggressive Reduction in Cholesterol Level (SPARCL) trial,2-4 and a recent meta-regression analysis.5 Despite this, guidelines do not specify target LDL-C levels due to the lack of adequate evidence from outcomes studies.1  Indeed, in routine clinical practice, many patients are prescribed low to moderate intensity statin therapy post-discharge and attain only moderate LDL-C reduction.6

 With the advent of highly efficacious LDL-C lowering therapies, such as PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, very low LDL-C levels are attainable (usually against a background of intensive statin therapy). Results from major outcomes studies with these agents have shown additional benefit in reducing residual stroke risk.7,8 These findings therefore underline the importance of comparing the effects of attainment of different target LDL-C levels on stroke risk, with a combination of both statin and non-statin therapies. 

 The results of the current Treat Stroke to Target trial in patients with recent ischaemic stroke or TIA and evidence of atherosclerotic disease, clearly show that attainment of a lower LDL-C target (<70 mg/dL versus 90-110 mg/dL) translates to reduction in subsequent CV events. Moreover, there was no heterogeneity in results seen in French versus Korean patients (albeit with reduced follow-up, median of 2.0 years versus 5.3 years in French patients). The other question regarding very low LDL-C levels pertains to safety. Both the SPARCL and Heart Protection studies,2,9 as well as meta-analysis of statin studies,10 had previously shown a numerically higher number of ICH events in individuals receiving intensive statin therapy, suggesting potential for increased risk. However, while there were numerically more ICH events in the lower LDL-C target group in the current study, the 95% CI suggested that there was no significant difference in risk between the two groups.

 The Treat Stroke to Target trial had a robust design and methodology. There are, however, limitations that may act as a caveat to the findings. Chief among these is the fact that the trial was prematurely halted after a median follow-up of 3.5 years, and the number of primary endpoints was less than that planned for in power calculations (277 versus 385 planned). Despite this, the study showed a significant reduction in the primary study endpoint with a 22% decrease in the relative risk of this endpoint with a lower than higher LDL-C target.  

 It is clear that despite best evidence-based medicine including statins, very high-risk patients including those with ischaemic stroke or TIA of atherosclerotic aetiology remain at high residual CV risk.6 One therapeutic strategy to address this residual risk is further lowering of LDL-C levels; the current study provides support for guideline recommendations for lower LDL-C targets. However, it is evident that even with a lower LDL-C target (against a background of best-evidence-based treatment), patients with an ischaemic stroke or TIA continue to experience major CV events, suggesting the need to consider other therapeutic targets. Mendelian randomization studies provide evidence to indicate remnant cholesterol as an additional target, showing a higher risk of ischaemic stroke in individuals with higher remnant cholesterol levels (≥1.5 mmol/l (58 mg/dl);11 this merits testing in clinical studies.

 In conclusion, the Treat Stroke to Target trial supports an LDL-C target ≤70 mg/dL in patients with a previous ischaemic stroke or TIA of atherosclerotic origin, to reduce the risk of subsequent major CV events. Whether the lower LDL-C target of <50 mg/dL (<1.4 mmol/L) recommended by current European guidelines for dyslipidaemia management,12 provides further reduction in the risk of ischaemic stroke requires testing.

References

1. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45: 2160-23.

2. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549-59.

3. Sillesen H, Amarenco P, Hennerici MG, et al. 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. Stroke 2008; 39: 3297-302.

4. Amarenco P, Goldstein LB, Szarek M, et al. 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. Stroke 2007; 38: 3198-204.

5. Shin J, Chung JW, Jang HS, et al. Achieved low-density lipoprotein cholesterol level and stroke risk: A meta-analysis of 23 randomised trials. Eur J Prev Cardiol 2019: doi: 10.1177/2047487319830503. [Epub ahead of print].

6. Amarenco P, Lavallée PC, Monteiro Tavares L, et al. Five-year risk of stroke after TIA or minor ischemic stroke. N Engl J Med 2018; 378: 2182-90.

7. Smith DA. Review: In dyslipidemia or atherosclerotic CVD, alirocumab and evolocumab vs control each reduce MI and stroke. Ann Intern Med 2019;171:JC56. doi: 10.7326/ACPJ201911190-056.

8. Salvatore T, Morganti R, Marchioli R, De Caterina R. Cholesterol lowering and stroke: no longer room for pleiotropic effects of statins - confirmation from PCSK9 inhibitor studies. Am J Med 2019; doi: 10.1016/j.amjmed.2019.06.029.

9. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22.

10. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388: 2532-61.

11. Varbo A, Nordestgaard BG. Remnant cholesterol and risk of ischemic stroke in 112,512 individuals from the general population. Ann Neurol 2019;85:550-9.

12. Mach F, Baigent C, Catapano AL et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2019. doi: 10.1093/eurheartj/ehz455. [Epub ahead of print]

Key words Treat Stroke to Target Study; ischaemic stroke; low-density lipoprotein cholesterol; lipid targets; residual cardiovascular risk