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NIHR Signal Short-term dual antiplatelet treatment may be best for most patients after receiving a drug-eluting stent

Published on 10 October 2019

doi: 10.3310/signal-000828

For patients who have had a drug-eluting stent inserted into the coronary arteries, there is no difference in mortality or cardiovascular outcomes between the standard 12-month dual antiplatelet therapy and shorter six-month courses. Longer courses above 12 months increased risk of bleeding and non-cardiac death compared with short courses.

It has been debated whether longer treatment might decrease complications, but similarly, it is unclear if shorter treatment might be as effective while reducing bleeding risk. This review included 17 trials assessing aspirin in combination with clopidogrel. Few trials assessed alternative second drugs.

This network meta-analysis shows that standard 12-month treatment might increase bleeding risk compared with six months’ treatment. With equivalent efficacy, shorter courses could be an option for more patients. However, the risk-benefit balance is close and needs to be considered on an individual basis. Longer treatment might still be preferable for some people with prior heart attack who are at higher risk of future cardiovascular events and low risk of bleeding.

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Why was this study needed?

Latest statistics from the British Heath Foundation show that there were around 310,000 hospital admissions for coronary heart disease in the UK in 2017/18. In 2015 there were 97,376 percutaneous coronary intervention procedures performed. 

Dual antiplatelet therapy, with aspirin and another drug, is the standard treatment for patients who have had a drug-eluting stent inserted into the coronary arteries. But the optimal duration for the use of the second drug has been questioned. Twelve months is standard for people who have had a stent for acute coronary syndrome, but recent evidence suggests that a six-month course may be just as effective. Shorter treatment may also decrease bleeding-related mortality and improve adherence.

This network meta-analysis aimed to assess the optimal duration of dual therapy, comparing treatment regimens directly within trials, and indirectly across trials.

What did this study do?

The systematic review identified 17 randomised controlled trials, including 46,864 adults who received dual antiplatelet therapy after receiving a drug-eluting stent.

Overall, 18,473 patients were assigned to standard-duration dual therapy (12 months), 13,234 to short-term dual therapy (six months) and 15,157 to long-term dual therapy (18 to 48 months). There was a good balance of direct treatment comparisons across outcomes, though slightly more trials compared standard and short-term dual therapy, with fewest directly comparing short vs long-term. All 17 trials included aspirin and clopidogrel dual therapy regimens and four of these trials also assessed prasugrel or ticagrelor as second drugs.

Trials were conducted in the US, Europe and Asia and published from 2010 to 2018. Around half contained potential risk for bias as patients or researchers were aware of treatment allocation. On other attributes trials were classified at low risk of bias.

What did it find?

  • Long-term dual therapy increased the risk of non-cardiac death compared with short-term therapy (odds ratio [OR] 1.63, 95% confidence interval (CI) CI 1.03 to 2.59), though there was no difference in the risk of all-cause mortality (OR 1.18, 95% CI 0.93 to 1.49) or cardiac mortality (OR 1.28, 95% CI 0.88 to 1.86). There was no difference between standard and short-term treatment for any mortality outcome.
  • Compared with short-term dual therapy, long-duration therapy increased the risk of both major bleeding (OR 1.78, 95% CI 1.27 to 2.49) and any bleeding (OR 2.13, 95% CI 1.46 to 3.10). Standard-term increased the risk of any bleeding compared with short-term, (OR 1.39, 95% CI 1.01 to 1.92). There was no difference between standard and short-term dual therapy for risk of major bleeding.
  • Long-term dual therapy decreased the risk of myocardial infarction (OR 0.63, 95% CI 0.46 to 0.86) or stent clotting (OR 0.57, 95%CI 0.34 to 0.95) compared with short-term. Again, there was no difference in either of these outcomes between short and standard-term dual therapy.
  • Subgroup analysis showed that, with the use of newer-generation drug-eluting stents, long-term dual therapy increased risk of all-cause mortality, major and any bleeding compared with short-term dual therapy. However, in patients who had had acute coronary syndrome, risk was only increased for any bleeding. This likely reflects the higher ischaemic risk for these patients compared to those with stable angina. However, short-term was equivalent to standard-term dual therapy, regardless of patient characteristics or type of stent.

What does current guidance say on this issue?

For people who have had a drug-eluting stent following acute coronary syndrome, NICE recommends dual therapy with aspirin (75-100mg) in combination with prasugrel (10mg daily), ticagrelor (90mg twice daily) or clopidogrel (75mg daily). Dual antiplatelet therapy is usually continued for up to 12 months, after which aspirin is continued alone.

For people who are at high risk of bleeding, dual therapy should be stopped at six months (prasugrel is also not recommended). NICE also says that for those who have tolerated 12 months of dual therapy without bleeding complications then dual therapy for up to 36 months (preferably with ticagrelor 60mg twice daily) can be considered, for example, those at higher risk of a future coronary event.

What are the implications?

These findings broadly support current recommendations to use 12 months’ dual therapy as standard, or six depending on bleeding risk. As six-month dual therapy appears to be as effective as standard 12-month therapy and potentially safer, the assessment of these risks and benefits become important for more patients.

It is also important to note that the evidence here relates to the length of dual therapy with clopidogrel after a drug-eluting stent.

Citation and Funding

Yin S, Xu P, Wang B et al. Duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stent: systematic review and network meta-analysis. BMJ; 2019,365:pl2222.

This project was supported by grants from the Major Science and Technology Project of Hunan Province (No 2016SK1001), The National Natural Science Foundation of China (No 81770403 and No 81470535) and National Key Research and Development Projects (No 2016YFC0900802).

Bibliography

British Heart Foundation. Heart and circulatory disease statistics 2019. London: British Heart Foundation; 2019.

NHS website. Coronary heart disease. London: Department of Health and Social Care; 2017.

NICE. Anti-platelet drugs: overview. Treatment summary. London: National Institute for Health and Care Excellence; undated.

NICE. Antiplatelet treatment. Treatment summary. London. National Institute for Health and Care Excellence. London; 2018.

Why was this study needed?

Latest statistics from the British Heath Foundation show that there were around 310,000 hospital admissions for coronary heart disease in the UK in 2017/18. In 2015 there were 97,376 percutaneous coronary intervention procedures performed. 

Dual antiplatelet therapy, with aspirin and another drug, is the standard treatment for patients who have had a drug-eluting stent inserted into the coronary arteries. But the optimal duration for the use of the second drug has been questioned. Twelve months is standard for people who have had a stent for acute coronary syndrome, but recent evidence suggests that a six-month course may be just as effective. Shorter treatment may also decrease bleeding-related mortality and improve adherence.

This network meta-analysis aimed to assess the optimal duration of dual therapy, comparing treatment regimens directly within trials, and indirectly across trials.

What did this study do?

The systematic review identified 17 randomised controlled trials, including 46,864 adults who received dual antiplatelet therapy after receiving a drug-eluting stent.

Overall, 18,473 patients were assigned to standard-duration dual therapy (12 months), 13,234 to short-term dual therapy (six months) and 15,157 to long-term dual therapy (18 to 48 months). There was a good balance of direct treatment comparisons across outcomes, though slightly more trials compared standard and short-term dual therapy, with fewest directly comparing short vs long-term. All 17 trials included aspirin and clopidogrel dual therapy regimens and four of these trials also assessed prasugrel or ticagrelor as second drugs.

Trials were conducted in the US, Europe and Asia and published from 2010 to 2018. Around half contained potential risk for bias as patients or researchers were aware of treatment allocation. On other attributes trials were classified at low risk of bias.

What did it find?

  • Long-term dual therapy increased the risk of non-cardiac death compared with short-term therapy (odds ratio [OR] 1.63, 95% confidence interval (CI) CI 1.03 to 2.59), though there was no difference in the risk of all-cause mortality (OR 1.18, 95% CI 0.93 to 1.49) or cardiac mortality (OR 1.28, 95% CI 0.88 to 1.86). There was no difference between standard and short-term treatment for any mortality outcome.
  • Compared with short-term dual therapy, long-duration therapy increased the risk of both major bleeding (OR 1.78, 95% CI 1.27 to 2.49) and any bleeding (OR 2.13, 95% CI 1.46 to 3.10). Standard-term increased the risk of any bleeding compared with short-term, (OR 1.39, 95% CI 1.01 to 1.92). There was no difference between standard and short-term dual therapy for risk of major bleeding.
  • Long-term dual therapy decreased the risk of myocardial infarction (OR 0.63, 95% CI 0.46 to 0.86) or stent clotting (OR 0.57, 95%CI 0.34 to 0.95) compared with short-term. Again, there was no difference in either of these outcomes between short and standard-term dual therapy.
  • Subgroup analysis showed that, with the use of newer-generation drug-eluting stents, long-term dual therapy increased risk of all-cause mortality, major and any bleeding compared with short-term dual therapy. However, in patients who had had acute coronary syndrome, risk was only increased for any bleeding. This likely reflects the higher ischaemic risk for these patients compared to those with stable angina. However, short-term was equivalent to standard-term dual therapy, regardless of patient characteristics or type of stent.

What does current guidance say on this issue?

For people who have had a drug-eluting stent following acute coronary syndrome, NICE recommends dual therapy with aspirin (75-100mg) in combination with prasugrel (10mg daily), ticagrelor (90mg twice daily) or clopidogrel (75mg daily). Dual antiplatelet therapy is usually continued for up to 12 months, after which aspirin is continued alone.

For people who are at high risk of bleeding, dual therapy should be stopped at six months (prasugrel is also not recommended). NICE also says that for those who have tolerated 12 months of dual therapy without bleeding complications then dual therapy for up to 36 months (preferably with ticagrelor 60mg twice daily) can be considered, for example, those at higher risk of a future coronary event.

What are the implications?

These findings broadly support current recommendations to use 12 months’ dual therapy as standard, or six depending on bleeding risk. As six-month dual therapy appears to be as effective as standard 12-month therapy and potentially safer, the assessment of these risks and benefits become important for more patients.

It is also important to note that the evidence here relates to the length of dual therapy with clopidogrel after a drug-eluting stent.

Citation and Funding

Yin S, Xu P, Wang B et al. Duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stent: systematic review and network meta-analysis. BMJ; 2019,365:pl2222.

This project was supported by grants from the Major Science and Technology Project of Hunan Province (No 2016SK1001), The National Natural Science Foundation of China (No 81770403 and No 81470535) and National Key Research and Development Projects (No 2016YFC0900802).

Bibliography

British Heart Foundation. Heart and circulatory disease statistics 2019. London: British Heart Foundation; 2019.

NHS website. Coronary heart disease. London: Department of Health and Social Care; 2017.

NICE. Anti-platelet drugs: overview. Treatment summary. London: National Institute for Health and Care Excellence; undated.

NICE. Antiplatelet treatment. Treatment summary. London. National Institute for Health and Care Excellence. London; 2018.

Duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stent: systematic review and network meta-analysis

Published on 30 June 2019

Yin, S. H.,Xu, P.,Wang, B.,Lu, Y.,Wu, Q. Y.,Zhou, M. L.,Wu, J. R.,Cai, J. J.,Sun, X.,Yuan, H.

Bmj Volume 365 , 2019

OBJECTIVE: To evaluate the efficacy and safety of standard term (12 months) or long term (>12 months) dual antiplatelet therapy (DAPT) versus short term (<6 months) DAPT after percutaneous coronary intervention (PCI) with drug-eluting stent (DES). DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Relevant studies published between June 1983 and April 2018 from Medline, Embase, Cochrane Library for clinical trials, PubMed, Web of Science, ClinicalTrials.gov, and Clinicaltrialsregister.eu. REVIEW METHODS: Randomised controlled trials comparing two of the three durations of DAPT (short term, standard term, and long term) after PCI with DES were included. The primary study outcomes were cardiac or non-cardiac death, all cause mortality, myocardial infarction, stent thrombosis, and all bleeding events. RESULTS: 17 studies (n=46 864) were included. Compared with short term DAPT, network meta-analysis showed that long term DAPT resulted in higher rates of major bleeding (odds ratio 1.78, 95% confidence interval 1.27 to 2.49) and non-cardiac death (1.63, 1.03 to 2.59); standard term DAPT was associated with higher rates of any bleeding (1.39, 1.01 to 1.92). No noticeable difference was observed in other primary endpoints. The sensitivity analysis revealed that the risks of non-cardiac death and bleeding were further increased for >/=18 months of DAPT compared with short term or standard term DAPT. In the subgroup analysis, long term DAPT led to higher all cause mortality than short term DAPT in patients implanted with newer-generation DES (1.99, 1.04 to 3.81); short term DAPT presented similar efficacy and safety to standard term DAPT with acute coronary syndrome (ACS) presentation and newer-generation DES placement. The heterogeneity of pooled trials was low, providing more confidence in the interpretation of results. CONCLUSIONS: In patients with all clinical presentations, compared with short term DAPT (clopidogrel), long term DAPT led to higher rates of major bleeding and non-cardiac death, and standard term DAPT was associated with an increased risk of any bleeding. For patients with ACS, short term DAPT presented similar efficacy and safety with standard term DAPT. For patients implanted with newer-generation DES, long term DAPT resulted in more all cause mortality than short term DAPT. Although the optimal duration of DAPT should take personal ischaemic and bleeding risks into account, this study suggested short term DAPT could be considered for most patients after PCI with DES, combining evidence from both direct and indirect comparisons. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018099519.

Expert commentary

There has been debate whether we should consider long-term dual antiplatelet therapy in patients with percutaneous coronary intervention using drug-eluting stents, to reduce the risk of adverse cardiovascular outcomes.

This important analysis concludes that short-term dual antiplatelet therapy could be considered for the majority of patients, given the minimal difference between short and long-term dual antiplatelet therapy for ischaemic outcomes, but an excess of bleedings with long-term dual antiplatelet therapy. Unsurprisingly, long-term use of any antithrombotic therapy (especially if in combination with an anticoagulant) will increase the propensity for bleeding.

There is the need for clear risk (re)assessment, recognising that ischaemic and bleeding risks are highly dynamic (and evolve over time), not a single ‘one-off’ assessment.

Gregory YH Lip, Price-Evans Chair of Cardiovascular Medicine, University of Liverpool; NIHR Senior Investigator

The commentator declares no conflicting interests