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Guan W, Lu H, Yang K. Choosing between ticagrelor and clopidogrel following percutaneous coronary intervention: A systematic review and Meta-Analysis (2007-2017). Medicine. 2018;97(43):e12978.

Study Population: Patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI)

Efficacy Endpoints

Death, heart attack, stroke

Harm Endpoints

Major bleeding and dyspnea

Narrative

Dual antiplatelet therapy with compared to aspirin alone after percutaneous coronary intervention modestly reduces nonfatal events like heart attack and stroke.1^, 2 This has led some to believe better antiplatelet agents could improve outcomes further, and ticagrelor has been proposed as such an agent.

The systematic review summarized here3 included 11 trials and 5 observational studies that in aggregate enrolled 25,805 subjects with acute coronary syndrome undergoing percutaneous coronary intervention as well as those with stable CAD. The patients included were predominantly male, with mean age 54-72 years old. The trials enrolled patients from United States, United Kingdom, Japan, Korea, Spain, Italy, France, Taiwan, and China.

Ticagrelor, as compared to clopidogrel, did not reduce heart attacks, strokes, deaths, or stent thrombosis, but did increase major bleeding (absolute risk difference [ARD]: 0.6%; odds ratio [OR]: 1.52; 95%CI, 1.01 - 2.29; Number-needed-to-harm [NNH]: 166). Major bleeding was defined as significant drop in hemoglobin (>3 g/dl) or requiring blood transfusion, or intra-ocular bleeding resulting in visual loss or complete blindness.3

More patients in the ticagrelor group experienced dyspnea (ARD: 7.6%, OR: 2.64, 95%CI, 1.87 - 3.72; NNH: 13), which could be one reason why there was a significantly higher rate of drug discontinuation in ticagrelor group (ARD: 1.7%, OR:5.67, 95%CI, 1.26 - 25.54; NNH: 59).3

Caveats

The evidence quality was variable, but most notably 5 observational studies were included. This is a methodologically important error, in our opinion. It is compounded by pooling them with trial data. This calls into question all results, particularly those which tended to hover near statistical significance. The observational data may have diluted or enhanced any effect. Some trials also included patients who suffer from stable CAD. However, a subgroup analysis that did not include these patients found similar results.

While based on the guidelines, patients undergoing PCI should be on dual antiplatelet therapy (asprin plus clopidogrel or ticagrelor), not all trials reported the exact number of patients on dual antiplatelets. However, the ones who reported the numbers, had nearly 100% of the patients on dual antiplatelet regimen.

Moreover, some individual trials in the meta-analysis report benefits for heart attack and mortality. The largest (PLATO, funded by ticagrelor’s manufacturer) included over 18000 subjects, finding a statistically significant 1.1% benefit for heart attack and 1.4% for mortality. Unlike most in the meta-analysis the trial followed the subjects for 12 months.4 This raises another limitation, follow up periods. Some reported one-month or in-hospital outcomes. Perhaps, therefore, short follow-up underestimated efficacy. This notion is challenged, however, by a nearly identical study of 800 subjects with 12 months follow-up, also funded by the maker of ticagrelor, which attempted to reproduce PLATO in an Asian setting, failed to find any benefit, and bordered on showing overall harm.5

Notably, ticagrelor (brand name Brilinta) is much more expensive than clopidogrel (Plavix). As of March 2019, the price for a one month supply of each was approximately $400 and $11, respectively.6

The 2016 ACC/AHA Guideline “Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease,” makes a class IIa recommendation that ticagrelor is preferential to clopidogrel for both non-ST-elevation acute coronary syndrome and ST-elevation myocardial infarction and patients who undergo percutaneous coronary intervention. We believe that the existing evidence does not support this recommendation, as there was no statistically significant benefit in stent re-thrombosis or all-cause mortality, while there was evidence of increased risk of harm compared to clopidogrel.7

In summary, the existing evidence is poor, includes observational data pooled with trial data, and finds only harm, no benefit, with ticagrelor. We have assigned a color recommendation of Red (No Benefits) because of the uncertainty about benefits and evidence of potential harms. We hope to see a more rigorous review as well as further relevant trials in the near future.

The original manuscript was published in Medicine by the Numbers, American Family Physician as part of the partnership between TheNNT.com and AFP.

Author

Donald Doukas, MD; Hannah Schimmer, NP; Shahriar Zehtabchi, MD

Published/Updated

April 15, 2019