Major Vascular Events

Long-term aspirin therapy for about 3 years reduced the risk ratio (RR) of serious vascular events (stroke, myocardial infarction (MI), or vascular death) by about 17% (95% confidence interval [CI]: 7–25%) compared with control (6.78%/yr aspirin vs 8.06%/yr control; RR 0.83, 95% CI: 0.75–0.93; absolute risk ratio [ARR] 1.28%/year; p = 0.001) (Table 19.1).

This corresponds to an absolute reduction in risk of serious vascular events of about 13/1000 per year (Antithrombotic Trialists’ Collaboration, 2009). There was no significant heterogeneity among the 10 trials (chi square 6.3; p = 0.7).

Any Recurrent Stroke

Long-term aspirin therapy for about 3 years reduced the RR of any recurrent stroke (ischaemic or haemorrhagic) by about 17% (95% CI: 4–28%) compared with control (3.90%/yr aspirin vs 4.68%/yr control; RR 0.83, 95% CI: 0.72–0.96; ARR 0.78% per year; p = 0.01) (see Table 19.1).

This corresponds to an absolute reduction in risk of recurrent stroke of about 8/1000 per year (Antithrombotic Trialists’ Collaboration, 2009). There was no significant heterogeneity among the 10 trials (chi square 8.4; p = 0.5).

Ischaemic Stroke

Long-term aspirin therapy was associated with a trend towards a reduction in RR of probable ischaemic stroke by about 23% (95% CI: –15–48%) compared with control (3.85%/yr aspirin vs 5.02%/yr control; RR 0.77, 0.52–1.15; ARR 1.17%) (Antithrombotic Trialists’ Collaboration, 2009).

Haemorrhagic Stroke

Long-term aspirin therapy increased RR of haemorrhagic stroke by about 2-fold compared with control (0.32%/yr aspirin vs 0.14%/yr control; RR 1.90, 1.06–3.44; absolute risk increase 0.18% per year) (Antithrombotic Trialists’ Collaboration, 2009).

Timing and Severity of Recurrent Stroke

An analysis of the individual patient data from all RCTs of aspirin after ischaemic stroke or TIA has offered insights into the effect of aspirin on the timing and severity of recurrent stroke.

Rothwell and colleagues found that in 12 trials of secondary prevention of stroke in 15,778 patients with TIA or ischaemic stroke randomized to aspirin or control, aspirin reduced the 12-week risk of any stroke by half (hazard ratio [HR] 0.49, 95% CI: 0.40–0.60), disabling or fatal ischaemic stroke by two-thirds (0.34, 0.25–0.46), and acute MI by two-thirds (0.30, 0.17–0.52) (Rothwell et al., 2016).

The effect of aspirin was consistent among the trials and independent of patient characteristics, stroke aetiology, and aspirin dose.

The effect of aspirin was, however, greater in the first 6 weeks after randomization (indeed, greatest in the first 2 weeks) than the second 6 weeks, and attenuated further to be of limited long-term benefit thereafter.

These results suggest that we might have underestimated the effect of aspirin in preventing early recurrent stroke and MI after TIA and ischaemic stroke, overestimated the effect of aspirin in preventing long-term recurrent stroke, and been unaware of the benefits of aspirin in reducing the severity of early recurrent ischaemic stroke.

Extracranial Haemorrhage

Aspirin was associated with a 2- to 3-fold increase in extracranial bleeding compared with control (0.25%/yr aspirin vs 0.06%/yr control; RR 2.69, 95% CI: 1.25–5.76: absolute risk increase [ARI] 0.19% per year). There was no significant heterogeneity among the 5 trials that recorded extracranial haemorrhage (chi square 3.6; p = 0.5) (Antithrombotic Trialists’ Collaboration, 2009).

Effects of Aspirin According to Body Weight and Dose

An analysis of the individual patient data from 117,279 participants enrolled in 10 randomized trials of aspirin in primary prevention of cardiovascular events revealed modifying effects of body weight (10-kg bands) on the effects of low doses (≤100 mg) and higher doses (300–325 mg or ≥500 mg) of aspirin (Rothwell et al., 2018).

Low doses of aspirin (75–100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. The ability of 75–100 mg aspirin to reduce cardiovascular events decreased with increasing weight (p-interaction = 0.0072), with benefit seen in people weighing 50–69 kg (HR 0.75 [95% CI 0.65–0.85]) but not in those weighing 70 kg or more (0.95 [0.86–1.04]; 1.09 [0.93–1.29] for vascular death). Higher doses of aspirin (≥325 mg) had the opposite interaction with body weight (difference p-interaction = 0.0013), reducing cardiovascular events only at higher weight (p-interaction = 0.017).

These data suggest that body weight should be considered when deciding on the dose of aspirin to be prescribed.

Non-responsiveness

The antiplatelet effect of aspirin may be compromised by patient non-adherence, decreased drug absorption, genetic polymorphisms, increased platelet turnover, increased platelet reactivity to other agonists, and exogenous thromboxane A2 from activated leucocytes or endothelium.

Serious Vascular Events

A systematic review of 9 RCTs of long-term dipyridamole versus control in 11,158 patients with previous ischaemic stroke or TIA revealed that long-term dipyridamole reduced the RR of serious vascular events (the composite event of vascular death, non-fatal MI, and non-fatal stroke) by about 14% (95% CI: 7–21%) compared with control (RR 0.86, 95% CI: 0.79–0.93) (De Schryver et al., 2007) (see Table 19.1).

Among 4 RCTs of long-term extended-release dipyridamole versus control in 9741 patients, the extended-release form of dipyridamole reduced the RR of serious vascular events by about 17% (95% CI: 9–24%) compared with control (RR, Mantel–Haenszel [M-H], Fixed: 0.83, 95% CI: 0.76–0.91) (De Schryver et al., 2007).

Stroke

A meta-analysis of individual patient data from RCTs of dipyridamole versus control in a total of 4913 patients with TIA and ischaemic stroke reported that, compared with control, assignment to dipyridamole was associated with an 18% (95% CI: 0–32%) reduction in odds of stroke (Leonardi-Bee et al., 2005).

Major Bleeding

Dipyridamole was not associated with an excess risk of major or fatal extracranial bleeding complications, compared with control, among 4 RCTs in a total of 3443 patients (RR: 0.76, 95% CI: 0.37–1.56) (De Schryver et al., 2007).

Headache

Dipyridamole was associated with an excess of headache, compared with control (37.2% dipyridamole vs 22.8% control) and was sufficiently severe to lead to discontinuation of study drug in the European Stroke Prevention Study (ESPS) 2 trial among 8.0% of patients assigned dipyridamole compared with 2.4% assigned placebo (RR 3.20, 95% CI: 2.25–4.54).

The headache is due to vasodilatation and is usually self-limited, but can occasionally last several weeks.

Dipyridamole may also cause gastrointestinal (GI) upset leading to discontinuation of study drug in some cases (placebo 3.6%, dipyridamole 6.2%; RR 1.65, 95% CI: 1.21–2.26), and may precipitate angina in patients with occlusive coronary artery disease by a steal effect.

Serious Vascular Events

In one RCT, the Cilostazol Stroke Prevention Study, involving 1095 patients with recent (1–6 months ago) ischaemic stroke, cilostazol 100 mg twice daily reduced the risk of serious vascular events by 38.8% (95% CI: 8.6–59.0) compared with placebo (4.2% per year cilostazol vs 6.8% per year placebo; ARR 2.6% per year; number needed to treat [NNT]: 38) (Gotoh et al., 2000).

Stroke

Cilostazol also reduced the risk of recurrent ischaemic stroke (the primary outcome) by 41.7% (95% CI: 8.6–59.0) in the Cilostazol Stroke Prevention Study (Gotoh et al., 2000).

Adverse Effects

Adverse effects of cilostazol included headache, tachycardia, and palpitations, which were probably related to its vasodilatory properties.

Serious Vascular Events

Among 13,380 high vascular risk patients enrolled in 15 RCTs, the combination of aspirin and dipyridamole significantly reduced the RR of serious vascular events (relative risk reduction [RRR] 26%, 95% CI: 20–32%) compared with control (RR 0.74, 95% CI: 0.68–0.80) (De Schryver et al., 2007).

Stroke

The combination of aspirin and dipyridamole was associated with a 39% (95% CI: 29–49%) reduction in odds of stroke compared with control (Leonardi-Bee et al., 2005).

Serious Vascular Events

The combination of aspirin and dipyridamole was associated with a 34% (25–43%) reduction in odds of serious vascular events compared with control (Leonardi-Bee et al., 2005).

Headache

The combination of aspirin and dipyridamole was associated with a greater incidence of headache compared with control (26.7% aspirin and dipyridamole vs 22.8% control).

Major Bleeding

The combination of aspirin and dipyridamole was associated with a greater incidence of any bleeding (8.1% aspirin and dipyridamole vs 4.2% control) compared with control (Leonardi-Bee et al., 2005).

Major Vascular Events

Among 3386 high vascular risk patients enrolled in 3 RCTs, there was no evidence that dipyridamole is more effective in preventing vascular events compared with aspirin (RR 1.02, 95% CI: 0.88–1.18) (De Schryver et al., 2007).

Skin Rash

Compared with aspirin, ticlopidine is associated with a 2-fold increase in the odds of skin rash (11.8% ticlopidine vs 5.5% aspirin, OR 2.2, 95% CI: 1.7–2.9)

Diarrhoea

Compared with aspirin, ticlopidine is associated with a 2-fold increase in the odds of diarrhoea (20.4% ticlopidine vs 9.9% aspirin, OR 2.3, 95% CI: 1.9–2.8).

Neutropenia

Compared with aspirin, ticlopidine is associated with a 3-fold excess of neutropenia (<1.2 × 10⁹/L) (2.3% ticlopidine vs 0.8% aspirin, OR 2.7, 95% CI: 1.5–4.8).

Thrombocytopenia

There are no published trial data available for the frequency of thrombocytopenia associated with ticlopidine compared with aspirin, but observational data have shown that ticlopidine is associated with a significant excess both of thrombocytopenia and of thrombotic thrombocytopenic purpura.

Serious Vascular Events

Clopidogrel significantly reduces the odds of serious ischaemic vascular events by about 9% (95% CI: 1–17%) compared with aspirin (see Figure 19.1) (CAPRIE Steering Committee, 1996; Sudlow et al., 2009).

Stroke

Clopidogrel was associated with a trend towards a reduction in risk of recurrent stroke compared with aspirin (RR 0.92, 95% CI: 0.80–1.07 (Gouya et al., 2014)) and odds of stroke compared with aspirin (OR 0.90, 95% CI: 0.77–1.06) (Sudlow et al., 2009), which is consistent with the effect observed for all thienopyridines (OR 0.90, 95% CI: 0.80–1.00) (see Figure 19.1) (Sudlow et al., 2009).

Figure 19.2 Forest plot showing the effects of thienopyridine derivatives (ticlopidine, clopidogrel) vs aspirin in patients with previous TIA or ischaemic stroke on stroke at the end of follow-up.

Reproduced from Sudlow et al. (2009) with permission from the authors and John Wiley & Sons Limited. Copyright Cochrane Library, reproduced with permission.

Serious Vascular Events

For patients with previous TIA or ischaemic stroke, clopidogrel does not significantly reduce the risk of serious vascular events compared with aspirin (RRR: 7.3%, 95% CI: −5.7 to 18.7%; OR 0.90, 0.77–1.06), but the results are consistent with the significant effect of clopidogrel compared with aspirin in all high-risk patients (Figure 19.2) (CAPRIE Steering Committee, 1996; Sudlow et al., 2009). These data are derived from one study, which was not designed to have the statistical power to reliably identify or exclude a modest but important treatment effect of clopidogrel in patient subgroups according to qualifying diagnoses (e.g. cerebrovascular disease) or outcome events (e.g. stroke) (CAPRIE Steering Committee, 1996). The trial was designed to have the statistical power to reliably identify or exclude a modest but important treatment effect of clopidogrel compared with aspirin in all high-risk patients combined for the composite outcome of major vascular events.

Gastrointestinal Haemorrhage

Clopidogrel was associated with significantly less GI haemorrhage (OR: 0.71, 95% CI: 0.6–0.9) and upper-GI symptoms (OR: 0.84, 95% CI: 0.8–0.9) compared with aspirin. However, these data are derived from one trial (CAPRIE trial) where patients were pre-selected as being tolerant of aspirin, and the dose of aspirin was 325 mg daily.

Skin Rash and Diarrhoea

Clopidogrel was also associated with a significant one-third increased odds of skin rash (OR: 1.32, 95% CI: 1.2–1.5) and diarrhoea (OR: 1.34, 95% CI: 1.2–1.6) compared with aspirin.

Non-reponsiveness

Non-responsiveness to clopidogrel is an issue for some individuals because clopidogrel is a prodrug that requires bioactivation by cytochrome P450 (CYP) isoenzymes to the active compound. Common reduced-function CYP2C19-2 and CYP2C19-3 polymorphisms and drug–drug interactions (e.g. PPIs) interfere with its bioactivation and antiplatelet effects. Other limitations of clopidogrel include a delayed onset and irreversibility of its antiplatelet effects.

Serious Vascular Events

A meta-analysis of two RCTs involving 3477 Asian participants reported that, compared with aspirin, cilostazol was associated with a significantly lower risk of composite outcome of vascular events (6.77% vs 9.39%, RR 0.72, 95% CI: 0.57–0.91). (Figure 19.3) (Kamal et al., 2011; Dinicolantonio et al., 2013).

Figure 19.3 Forest plot showing the effects of cilostazol vs aspirin in patients with previous TIA or ischaemic stroke on serious vascular events (stroke, MI, or vascular death) at the end of follow-up.

Reproduced from Kamal et al. (2011) with permission from the authors and John Wiley & Sons Limited. Copyright Cochrane Library, reproduced with permission.

Stroke

Cilostazol was associated with a lower risk of all stroke (RR 0.67, 95% CI: 0.52–0.86), and haemorrhagic stroke (0.53% vs 2.01%, RR 0.26, 95% CI: 0.13–0.55), and a non-significant trend towards a reduction in ischaemic stroke (RR 0.80, 95% CI: 0.67–1.07), compared with aspirin (Kamal et al., 2011).

Extracranial Haemorrhage

Cilostazol was associated with less extracranial haemorrhage during follow-up compared to aspirin (RR 0.74, 95% CI: 0.61–0.90) (Figure 19.4) (Kamal et al., 2011).

Figure 19.4 Forest plot showing the effects of cilostazol vs aspirin in patients with previous TIA or ischaemic stroke on extracranial haemorrhage at the end of follow-up.

Reproduced from Kamal et al. (2011) with permission from the authors and John Wiley & Sons Limited. Copyright Cochrane Library, reproduced with permission.

Minor Adverse Effects

Compared with aspirin, cilostazol was significantly associated with minor adverse effects (8.22% vs 4.95%, RR 1.66, 95% CI: 1.51–1.83) (Figure 19.5).

Figure 19.5 Forest plot showing the effects of cilostazol vs aspirin in patients with previous TIA or ischaemic stroke on adverse effects at the end of follow-up.

Reproduced from Kamal et al. (2011) with permission from the authors and John Wiley & Sons Limited. Copyright Cochrane Library, reproduced with permission.

TIA and Ischaemic Stroke Patients

Serious Vascular Events

Among 2944 patients with stroke or TIA who were enrolled in 4 RCTs of triflusal vs aspirin and followed for 6 to 47 months, there was no significant difference in the rate of serious vascular events between triflusal and aspirin; the odds ratio (OR) for serious vascular events among patients assigned aspirin compared to triflusal was 1.02 (95% CI: 0.83–1.26) (Figure 19.6) (Costa et al., 2005).

Figure 19.6 Forest plot showing the effects of triflusal vs aspirin in patients with previous ischaemic stroke or acute myocardial infarction on serious vascular events at the end of follow-up.

Reproduced from Costa et al. (2005) with permission from the authors and John Wiley & Sons Limited. Copyright Cochrane Library, reproduced with permission.

Intracranial Haemorrhage or Other Major Systemic (extracranial) Haemorrhage

In three RCTs of triflusal vs aspirin in a total of 2753 stroke patients, aspirin was associated with a significant increase in the composite outcome of intracranial haemorrhage or major systemic (extracranial) haemorrhage compared to triflusal (OR 2.42, 95% CI: 1.56–3.77) (Figure 19.7) (Costa et al., 2005).

Figure 19.7 Forest plot showing the effects of triflusal vs aspirin in patients with previous ischaemic stroke or acute myocardial infarction on any intracranial haemorrhage or other major systemic haemorrhage at the end of follow-up.

Reproduced from Costa et al. (2005) with permission from the authors and John Wiley & Sons Limited. Copyright Cochrane Library, reproduced with permission.

Ischaemic Stroke Patients

Among 19,120 patients with a recent non-cardioembolic ischaemic stroke (<3 months) or TIA (<8 days), random allocation to terutroban 30 mg per day for a mean of 28.3 months (standard deviation [SD] 7.7) was associated with no reduction in ischaemic stroke, MI, or vascular death (excluding haemorrhagic death) compared with aspirin 100 mg per day (11% vs 11%; HR 1.02, 95% CI: 0.94–1.12) but an increase in minor bleeding (12% vs 11%; HR 1.11, 95% CI: 1.02–1.21) (Bousser et al., 2011).

High Vascular Risk Patients

A recent Cochrane systematic review identified 15 RCTs comparing over 30 days’ use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in 33,970 people with coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease, but not having a coronary stent (Squizzato et al., 2017; Donadini et al., 2018).

Ischaemic Stroke

Aspirin plus clopidogrel was associated with a reduction in the risk of fatal and non-fatal ischaemic stroke compared with aspirin (RR 0.73, 95% CI: 0.59–0.91; participants = 4006; studies = 5; moderate quality evidence) (Figure 19.8).

Figure 19.8 Forest plot showing the effects of clopidogrel vs aspirin in high vascular risk patients (CHARISMA) or patients with acute myocardial infarction (CURE) on serious vascular events at the end of follow-up.

Reproduced from Squizzato et al. (2017) with permission from the authors and John Wiley & Sons Limited. Copyright Cochrane Library, reproduced with permission.

Myocardial Infarction

There was a lower risk of fatal and non-fatal MI with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 0.78, 95% CI: 0.69–0.90; participants = 16,175; studies = 6; moderate quality evidence).

Mortality

There was no difference in the effectiveness of aspirin plus clopidogrel in preventing cardiovascular mortality (RR 0.98, 95% CI: 0.88–1.10; participants = 31,903; studies = 7; moderate quality evidence), and no evidence of a difference in all-cause mortality (RR 1.05, 95% CI: 0.87–1.25; participants = 32,908; studies = 9; low quality evidence).

Major and Minor Bleeding

There was a higher risk of major bleeding with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 1.44, 95% CI: 1.25–1.64; participants = 33,300; studies = 10; moderate quality evidence) and of minor bleeding (RR 2.03, 95% CI: 1.75–2.36; participants = 14,731; studies = 8; moderate quality evidence).

Net Effect in High Vascular Risk Patients

The addition of clopidogrel to aspirin compared with aspirin alone in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent was associated with 23 (95% CI: 7–39) fewer cases of ischaemic stroke and 13 (95% CI: 6–19) fewer cases of MI for every 1000 patients treated during a median period of 12 months, but also with an increase of 9 (95% CI: 6–12) cases of major bleeding during a median period of 10.5 months

According to Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, the quality of evidence was moderate for all outcomes except all-cause mortality (low-quality evidence) and adverse events (very low-quality evidence).

Prior Ischaemic Stroke or TIA

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial randomly assigned 15,603 patients with either clinically evident cardiovascular disease (n = 12,153) or multiple atherothrombotic risk factors (n = 3284) to receive clopidogrel (75 mg per day) plus low-dose aspirin (75–162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months (Bhatt et al., 2006).

A total of 4320 patients with prior ischaemic stroke (n = 3245) or TIA (1233) within the previous 5 years were enrolled in the CHARISMA trial (Hankey et al., 2011).

Related posts:

Chapter 5 – Supportive Care during Acute Cerebral Ischaemia Chapter 12 – Neuroprotection for Acute Brain Ischaemia Chapter 9 – Acute Antiplatelet Therapy for the Treatment of Ischaemic Stroke and Transient Ischaemic Attack Chapter 18 – Drugs, Devices, and Procedural Therapies to Prevent Recurrent Cardiogenic Embolic Stroke Chapter 25 – Using Pharmacotherapy to Enhance Stroke Recovery Chapter 26 – Electrical and Magnetic Brain Stimulation to Enhance Post-stroke Recovery

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