Treatments for the secondary prevention of stroke and TIA.
Smoking cessation
Smokers have 3 times the risk of stroke compared to non-smokers.
Physical activity
Cardiorespiratory training programmes can improve functional capacity. A 2020 Cochrane review found that2:
Diet
A Mediterranean diet has been shown to reduce myocardial infarction and total mortality in patients with CHD.
Although there is no evidence of its effect in reducing stroke risk, the RCP stroke guidelines recommend it to those who have had a stroke or TIA1.
Alcohol
In the general population, the risk of stroke increases with alcohol consumption over 3 units per day
Low alcohol intake of 1-2 units per day is associated with a reduced risk of stroke (Relative Risk Reduction 15%)3.
VERY LOW quality evidence
References
1)Intercollegiate Stroke Working Party. National clinical guideline for stroke: 5th edition. London: Royal College of Physicians; 2016
2)Saunders D, Sanderson M, Hayes S et al. Physical fitness training for stroke patients. Cochrane Database of Systematic Reviews 2020, Issue 3. Art. No.: CD003316.
3)Zhang C, Qin Y-Y, Chen Q et al. Alcohol intake and risk of stroke: a dose-response meta-analysis of prospective studies. International Journal of Cardiology 2014; 174(3): 669-677
NICE recommends clopidogrel 75mg as first choice antiplatelet therapy following a stroke:
There are no trials comparing clopidogrel with placebo. You can get an idea of their additive effect from the data below comparing:
Aspirin v placebo
Figures derived from from a single trial:
Clopidogrel v aspirin
Figures derived from a single trial:
Clopidogrel v aspirin+MR dipyridamole
A further trial (data not shown in graphics):
General note
There are many trials on antiplatelet agents in vascular disease, which are a mixed bag of treatment and patient-types. These example trials were chosen for simplicity, from systematic reviews performed by the Antithrombotic Treatment Triallists Collaboration4 and for NICE5.
References
1)The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338(8779): 1345-9
2)CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348(9038): 1329-1339
3)Sacco RL, Diener H-C, Yusuf S et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008; 359: 1238–1251
4)Antithrombotic treatment triallists’ collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373(9678): 1849-1860
5)Greenhalgh J, Bagust A, Boland A et al. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events. Health Technology Assessment 2011; 15(31): 1-178
| This research provides a good indication of the treatment effect.
There is a moderate possibility that the true effect is smaller or greater. |
The figures shown above are derived from 2 trials1,2 both at low risk of bias, however:
References
1)The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338(8779): 1345-9
2)CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348(9038): 1329-1339
3)Antithrombotic treatment triallists’ collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373(9678): 1849-1860
4)Greenhalgh J, Bagust A, Boland A et al. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events. Health Technology Assessment 2011; 15(31): 1-178
The population characteristics in these 2 trials were:
| Aspirin v placebo1 | Clopidogrel v aspirin2 |
|
|
References
1)The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338(8779): 1345-9
2)CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348(9038): 1329-1339
Clopidogrel
2 in 100 people taking clopidogrel 75mg od had a GI bleed over 3 years in the CAPRIE trial2:
Bleeding risk with standard dose aspirin alone for comparison
1 in 200 people will experience a major bleed due to aspirin therapy over the course of 5 years treatment1:
Aspirin+dipyridamole v clopidogrel
Aspirin+dipyridamole are associated with more side effects than clopidogrel in the major trial comparing the two3:
| Aspirin+modified-release dipyridamole | Clopidogrel | |
| Major bleed* | 4.1% | 3.6% |
| Headache | 5.9% | 0.9% |
| Nausea or vomiting | 1.6% | 0.5% |
| Diarrhoea | 1% | 0.4% |
| Dizziness | 1.3% | 0.5% |
*Major bleed – requiring hospitalisation, 2 units blood transfusion, resulting in disability or symptomatic intra-cranial haemorrhage
References
1)Selak V, Jackson R, Poppe K et al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease. A cohort study. Annals of Internal Medicine 2019; 170(6): 357-368
2)CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348(9038): 1329-1339
3)Sacco RL, Diener H-C, Yusuf S et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008; 359: 1238–1251
NICE recommends atorvastatin 80mg for the secondary prevention of cardiovascular disease (CHD and stroke/TIA).
Figures derived from a single trial (SPARCL):
This trial was included in the 2014 NICE guideline evidence review (current for the 2018 guideline)1:
1)National Institute for Health and Care Excellence. Cardiovascular disease: Risk Assessment and reduction, including lipid modification 2014 [Internet]. [London]: NICE; 2014 [updated 2016 Sep]. (Clinical guideline [CG181]).
2)The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–559
| This research provides a very good indication of the treatment effect.
However, it is possible that the true effect is slightly smaller or greater. |
NICE rated this evidence as HIGH quality1:
The SPARCL trial was individually rated at low risk of bias2.
1)National Institute for Health and Care Excellence. Cardiovascular disease: Risk Assessment and reduction, including lipid modification 2014[Internet]. [London]: NICE; 2014 [updated 2016 Sep]. (Clinical guideline [CG181]).
2)The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–559
The population characteristics in the SPARCL trial1 were:
Reference
1)The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–559
The recommendation to prescribe atorvastatin 80mg in secondary prevention comes from a committee decision in the overall NICE evidence review1 which shows increasing benefit from higher intensity statins.
There is no direct comparison of Atorvastatin 80mg v (say) Atorvastatin 20mg in patients who have had recent strokes or TIAs.
1)National Institute for Health and Care Excellence. Cardiovascular disease: Risk Assessment and reduction, including lipid modification 2014 [Internet]. [London]: NICE; 2014 [updated 2016 Sep]. (Clinical guideline [CG181])
Muscle pains and general malaise are sometimes reported with statin use. Most of this (roughly 90%) is due to a nocebo* effect.
* an adverse effect experienced because the patient expects it, rather than as a result of the treatment itself
more
This has been controversial over the years with some arguing that they are not genuine side effects because:
Others argued that7:
The question has perhaps been resolved by 2 trials set in the UK, involving patients who had previously reported muscle aches or other side effects with statins10,11. They were given statins, placebo or no tablets for periods of 1-2 months in random order and asked to record their symptoms.
Both trials, which were fully blinded and well conducted, showed that muscle symptoms and other “side effects” (even ones severe enough to stop taking the tablets) were almost as common with placebo tablets. Half to two-thirds of patients were able to restart their statins after receiving feedback.
2-22 excess cases per 10,000 person years for both combined3.
more
The NICE systematic review of RCTs did not find evidence of an increase in these side effects1.
However, RCTs can fail to pick up rare harms. Observational research (LOW quality evidence) has shown the following risks:
Myositis (muscle pain plus elevated CK x 10)
Rhabdomyolysis (severe myopathy with extremely elevated CK, myoglobinaemia and renal impairment)
4 in every 1000 people will develop raised transaminases (ALT >3 x normal) due to taking a statin.
Statin-related raised transaminases up to 3 x the upper limit of normal are thought to be harmless and do not require statin therapy to be stopped if stable1.
more
This approximate figure is found by both the NICE systematic review of RCTs (who rated it MODERATE quality evidence)1 and a Cochrane review of observational studies2.
Acute hepatitis and liver failure associated with statins are so rare it is uncertain whether there is a causal effect.
more
RCT data has not shown an increase in these harms compared to placebo. A 2007 review paper5 said:
‘Although hepatitis and liver failure have been reported spontaneously and from trials of statins, it is not clear whether they are causally related or that the risk is over and above the background risk of sporadic liver failure.’
1 excess case per 200 people over a 5 year period due to taking a statin.
However, the cardiovascular benefits of statins outweigh risks associated with glycaemic changes5.
Statins do not need to be stopped in response to increases in blood glucose or HbA1c1.
more
This number comes from the NICE evidence review of RCTs and was rated as HIGH quality evidence1. A similar figure was produced in another large systematic review of RCTs2.
Larger risks have been reported in observational studies (up to 2% per annum), though this was described as weak evidence by the Cochrane review group undertaking the analysis3.
Larger risks (up to a few percent over 5 years) have been shown in RCTs using atorvastatin 80mg. This was in subgroups with 2 or more risk factors for diabetes. Not all findings were statistically significant so there is uncertainty about the size of the effect4.
References
more
1)National Institute for Health and Care Excellence. Cardiovascular disease: Risk Assessment and reduction, including lipid modification 2014 [Internet]. [London]: NICE; 2014 [updated 2016 Sep]. (Clinical guideline [CG181])
2)Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375(9716): 735-742
3)Macedo AF, Taylor FC, Casas JP et al. Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC Med 2014; 12: 51
4)Waters DD, Ho JE, DeMicco D et al. Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin: Results From 3 Large Randomized Clinical Trials. J Am Coll Cardiol 2011; 14: 1535-1545
5)Armitage J. The safety of statins in clinical practice. Lancet 2010; 370(9601): 1781-1790
6)Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388(10059): 2532-2561
7)Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013; 347 :f6123
8)Buettner C, Davis RB, Leveille SG et al. Prevalence of musculoskeletal pain and statin use. J Gen Intern Med 2008 Aug; 23(8): 1182-1186
9)Mansi I, Frei CR, Pugh MJ et al. Statins and Musculoskeletal Conditions, Arthropathies, and Injuries. JAMA Intern Med 2013; 173(14): 1318–1326
10)Wood FA, Howard JP, Finegold JA et al. N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects. N Engl J Med 2020; 383: 2182-2184
11)Herrett E, Williamson E, Brack K et al. Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials BMJ 2021; 372 :n135
NICE recommends a standard BP treatment target of 140/90mmHg for people who have had a stroke or TIA1.
You may have heard recommendations for lower targets; the Royal College of Physicians recommend a target systolic blood pressure of 130mmHg2.
Summary
Further details on the evidence
more
A key trial published in 2013 (SPS3)3 found a 1.6% absolute risk reduction in stroke after 3 1/2 years:
A 2018 Cochrane review6 also explored this question, and analysed the SPS3 trial alongside some smaller studies. They found:
The RCP guideline also interpreted general research into low BP targets (including the SPRINT study4 and another meta-analysis5) in a favourable light to support their recommendation. This area has been controversial – see the section on general Hypertension/BP targets for more information on the possible benefits and harms of low BP targets.
References
more
1)National Institute for Health and Care Excellence. Hypertension in adults: diagnosis and management[Internet]. [London]: NICE; 2019. (NICE guideline [NG136])
2)Intercollegiate Stroke Working Group Party. National Clinical Guideline for Stroke. Royal College of Physicians 2016. Accessed online May 2022
3)The SPS3 Study Group. Blood‐pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382(9891): 507‐515
4)A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015; 373: 2103-2116
5)Ettehad D, Emdin CA, Kiran A et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387(10022); 957-67
6)Zonneveld TP, Richard E, Vergouwen MDI et al. Blood pressure‐lowering treatment for preventing recurrent stroke, major vascular events, and dementia in patients with a history of stroke or transient ischaemic attack. Cochrane Database of Systematic Reviews 2018, Issue 7. Art. No.: CD007858.
People who have an adverse event
People whose adverse event is prevented by treatment
People who were never going to have an adverse event anyway
Graphics and NNTs are rounded to the nearest integer
These three statistical terms offer three different ways of looking at the results of trial data.
Absolute Risk Reduction
This tells you how many people out of 100 who take a treatment have an adverse event prevented.
MoreThe value of the ARR changes with the baseline risk of the person (or population) taking the treatment. The higher the starting risk, the greater the absolute chance of benefit.
You need to think about over what time the trial data show this benefit, as it is usually assumed that more absolute risk reduction is gained over time.
Your patient might be taking the treatment for much longer than the length of a clinical trial (or, if life expectancy is limited, perhaps for less time).
Number Needed to Treat
This tells you how many people need to take the treatment in order for one person to avoid an adverse event.
The lower the number, the more effective the treatment.
MoreThe value of the NNT changes with the baseline risk of the person (or population) taking the treatment. The higher the starting risk, the smaller the NNT.
You need to think about over what time the trial data show benefit, as it is usually assumed that more benefit is gained over time and therefore the NNT will drop over time.
Your patient might be taking the treatment for much longer than the length of a clinical trial (or, if life expectancy is limited, perhaps for less time).
Relative Risk Reduction
This tells you the proportion of adverse events that are avoided if the entire population at risk is treated.
MoreThe value of the RRR is usually constant in people (or populations) at varying degrees of risk.
It is also usually assumed to stay constant over time.
This can be helpful, especially when thinking about population outcomes, but can be misleading for an individual person:
For example, a RRR of 25% in someone with a baseline risk of 40% would give them an ARR of 10% and an NNT of 10.
A RRR of 25% in someone with a baseline risk of 4% would give them an ARR or 1% and an NNT of 100.
This website is designed for use by General Practitioners and other healthcare professionals. The content is not exhaustive and assumes a standard level of GP professional knowledge. The information here is intended to support clinical judgement and shared decision making alongside clinical guidelines and standard practice.
If you are a patient/member of the public, do feel free to look around, but please don’t make any changes to your treatments based on information here. If you find something which seems relevant to you, you could show this website to your healthcare professional to help a discussion.