Full transparency of ticagrelor trials in coronary artery disease should be warranted

KEYWORDS:

• Ticagrelor
• randomized controlled trial
• transparency
• clopidogrel

When Omeprazole’s patent expired in 2001, the product-switching strategy to its nearly identical, patent-protected drug Esomeprazole was an economic disaster for citizens and consumers, yet enormously profitable for AstraZeneca [1]. Two decades later, despite weak evidence of clinical superiority (Table 1), pricey ticagrelor, also marketed by AstraZeneca, has replaced the inexpensive clopidogrel. It is associated with higher rates of side effects [2], and the b.i.d. administration does not facilitate treatment adherence for patients with acute coronary syndromes (ACS). Nevertheless, guidelines strongly recommend and support usage of ticagrelor in ACS patients [3]. In times of economic crisis, the switch from ticagrelor to clopidogrel after 1 month of treatment should be at least considered by doctors.

Table 1. Designs of the trials discussed within manuscript

TRIALS	POPULATION, MEAN AGE	INTERVENTION	COMPARATOR	MEAN or MEDIAN DURATION	PRIMARY OUTCOME	Results for the primary outcome
PLATO[4]	18,624 patients (62 years old) admitted to the hospital with an ACS	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter)	Clopidogrel (300–600 mg loading dose, 75 mg daily thereafter)	12 months	Death from vascular causes, MI, or stroke	At 12 months, the primary end point had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (HR 0.84; 95% CI 0.77 to 0.92; P < .001).
PHILO[8]	801 patients with ACS	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter)	Clopidogrel (300–600 mg loading dose, 75 mg daily thereafter)	12 months	Primary safety and efficacy endpoints were time to first occurrence of any major bleeding event and to any event from the composite of MI, stroke or death from vascular causes, respectively	At 12 months, overall major bleeding occurred in 10.3% of ticagrelor-treated patients and in 6.8% of clopidogrel-treated patients (HR 1.54; 95% CI 0.94–2.53); the composite primary efficacy endpoint occurred in 9.0% and in 6.3% of ticagrelor- and clopidogrel-treated patients, respectively (HR 1.47; 95% CI 0.88–2.44).
PEGASUS-TIMI54[10]	21,162 patients (65.4 years-old) who had a MI 1–3 years earlier	Ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily	Placebo	2.75 years	CV death, MI, or stroke	The rate of the primary efficacy end point, with Kaplan–Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (HR for 90 mg of ticagrelor vs. placebo, 0.85; 95% CI 0.75 to 0.96; P = .008; HR for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI 0.74 to 0.95; P = .004).
THEMIS[11]	19,220 patients who were 50 years of age or older and who had stable CAD and type 2 diabetes mellitus	Ticagrelor initially 90 mg then 60 mg twice daily plus aspirin	Placebo plus aspirin	39.9 months	CV death, MI, or stroke	The incidence of the primary efficacy outcome was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; HR 0.90; 95% CI 0.81–0.99; P = .04)
TICAKOREA[9]	800 Korean patients hospitalized for ACS with or without ST elevation and intended for invasive management	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter)	Clopidogrel (600 mg loading dose, 75 mg daily thereafter)	12 months	Clinically significant bleeding (composite of major bleeding or minor bleeding according to PLATO (Platelet Inhibition and Patient Outcomes) criteria at 12 months Co-primary net clinical benefit outcome consisted of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding	At 12 months, the incidence of clinically significant bleeding was significantly higher in the ticagrelor group than in the clopidogrel group (11.7% [45/400] vs 5.3% [21/400]; HR 2.26; 95% CI 1.34 to 3.79; P = .002). The incidence of death from CV causes, MI, or stroke was not significantly different between the ticagrelor group and the clopidogrel group (9.2% [36/400] vs 5.8% [23/400]; HR 1.62; 95% CI 0.96 to 2.74; P = .07).
ALPHEUS[12]	1,910 patients with stable coronary artery disease and had an indication for PCI and at least one high-risk characteristic	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter for 30 days)	Clopidogrel (300–600 mg loading dose, 75 mg daily thereafter for 30 days)	48 hours	Composite of PCI-related type 4 (a or b) MI or major myocardial injury and the primary safety outcome was major bleeding, both of which were evaluated within 48 h of PCI (or at hospital discharge if earlier).	At 48 h, the primary outcome was observed in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group (OR 0.97, 95% CI 0.80–1.17; P = .75)
POPular AGE[13]	1,002 Patients aged 70 years or older with NSTE-ACS	Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) in 95% Prasugrel 60 mg loading dose, 10 mg daily thereafter) in 5%	Clopidogrel (300–600 mg loading dose, 75 mg daily thereafter)	12 months	Primary bleeding outcome consisted of PLATelet inhibition and patient Outcomes (PLATO; major or minor bleeding [superiority hypothesis])	Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; HR 0.71, 95% CI 0.54 to 0.94; P = .02 for superiority). Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; ARD −4%, 95% CI −10.0 to 1.4; P = .03 for non-inferiority)
TOPIC[16]	645 patients admitted with ACS requiring coronary intervention, on aspirin and a newer P2Y12 blocker (ticagrelor 43%, prasugrel 57%) and without adverse event at 1 month, were assigned to switch to aspirin and clopidogrel (switched DAPT) or continuation of their drug regimen (unchanged DAPT).	Continuation of their drug regimen (unchanged DAPT).	Switch to aspirin and clopidogrel (switched DAPT)	12 months	Composite of CV death, urgent revascularization, stroke and bleeding as defined by the Bleeding Academic Research Consortium (BARC) classification ≥2 at 1 year post ACS.	The primary endpoint occurred in 43 (13.4%) patients in the switched DAPT group and in 85 (26.3%) patients in the unchanged DAPT (HR 95%CI 0.48 (0.34–0.68), P < 0.01). No significant differences were reported on ischemic endpoints, while BARC ≥ 2 bleeding occurred in 13 (4.0%) patients in the switched DAPT and in 48 (14.9%) in the unchanged DAPT group (HR 95%CI 0.30 (0.18–0.50), P < .01)

Abbreviations ARD: absolute risk difference; FI: fragility index; MI: myocardial infarction; ACS: acute coronary syndrome; CV: cardiovascular; DAPT: dual antiplatelet therapy; HF: heart failure; HR: hazard ratio; LV: left ventricular; MI: myocardial infarction; NSTE: non ST elevation; NYHA: New York Heart Association; NNT: number needed to treat for the primary outcome during the mean duration follow-up of the study; OR: odds ratio

The seminal Platelet Inhibition and Patient Outcomes (PLATO) trial [2] randomized 18,624 ACS patients to ticagrelor (loading dose of 180 mg followed by 90 mg twice daily) or to a suboptimal loading dose of clopidogrel followed by 75 mg daily [4]. Overall, the clopidogrel optimal loading dose of 600 mg was only administered to one-fifth of ACS patients, in 35.6% of the 7,544 patients with ST-elevation ACS or new or unknown left bundle branch block. The 508 ACS patients who were taking clopidogrel for >5 days before randomization were not eligible for a loading dose of clopidogrel. Overall, the difference in events between the ticagrelor and clopidogrel arms was 150 (9.8 versus 11.7%, hazard ratio (HR) 0.84 [0.77, 0.92]), with a mean number needed to treat to delay one adverse outcome beyond the trial duration (NNT) of 53, but this was not significant in the ST-elevation ACS subgroup (9.4 versus 10.8%, HR 0.87 [0.75, 1.01]). Outcome postponement is the adverse event-free time interval, as displayed by the time difference between survival curves [5]. Ticagrelor postponed cardiovascular death, MI, or stroke by 4.9 days during 1-year of trial running time compared to clopidogrel. The fragility index quantifies how many patients would be required to convert a trial from significant to not significant (P ≥ .05). While the fragility index of the PLATO study is 79, PLATO investigators failed to report the rate of loss of follow-up (LFU) in the main publication and in the supplementary material. The following review by US Food and Drug Administration (FDA) indicated a LFU number of more than 2,600 PLATO patients, a number that largely exceeds the fragility index [6]. Both the PHILO and TICAKOREA trials duplicated the design of PLATO in Asian ACS patients but did not find similar results [7,8]. Of note, in the PLATO study, the HR value found in the 1,814 North-American patients (1.25 [0.93 to 1.67]) differed from that found in patients from other geographic regions enrolled in PLATO [2].

The Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) enrolled 21,162 MI patients and compared ticagrelor to placebo but not to the effective comparator clopidogrel [9]. The NNT = 79 for ticagrelor 60 mg over a mean 2.75-year duration. Ticagrelor postponed cardiovascular death, MI, or stroke by 8.5 days during 3 years of PEGASUS-TIMI trial running time [9]. Of note, ticagrelor was compared to placebo also in high-risk patients with diabetes and stable coronary artery disease (CAD) in the THEMIS trial, achieving a high NNT of 115 over the 3.3-year trial duration, a low outcome postponement of 8.3 days along with a fragility index of nine events compared with the 21 LFU patients [10]. In addition, the short-term ALPHEUS trial did not find superiority of ticagrelor over clopidogrel in high-risk patients with stable CAD who underwent percutaneous coronary intervention [11].

The POPular AGE trial noted fewer bleeding events without an increase in the combined endpoint of all-cause death, MI, stroke, and bleeding with clopidogrel compared to ticagrelor or prasugrel in patients >70 years old with ACS [12].

Real-world registries have provided external validity for the findings of RCTs. Major databases from population-based cohort studies have found that ticagrelor use was not associated with a statistically significant reduction in MACE vs clopidogrel (adjusted HR 0.97 [0.85 to 1.10]); however, ticagrelor was consistently associated with more bleeding events (adjusted HR 1.51 [1.29 to 1.78]), more dyspnea (adjusted HR 1.98 [1.47 to 2.65]), and thus more emergency department visits and impaired quality of life [13]. You and coworkers found similar results in another cohort of 62,580 propensity score–matched patients [14]. Side effects may in turn result in early discontinuation of ticagrelor.

Finally, both TOPIC [15] and TALOS-AMI [16] RCTs have demonstrated that the de-escalation strategy of dual antiplatelet therapy including switching from ticagrelor to clopidogrel reduced bleeding events without increasing ischemic events or mortality.

In summary, a fair comparison of ticagrelor to clopidogrel is needed in patients with ACS. Safe and cost-effective switching from ticagrelor to clopidogrel after 1 month may allow ACS patients to afford long-term dual antiplatelet therapy and/or decrease public healthcare costs. Moreover, lack of transparency over LFU, disagreement between centrally adjudicated and site-reported events, and excess mortality in the PLATO patients should trigger an independent audit [17]. Full disclosure of AstraZeneca records should be mandated as politic unusually intervened to urge for more ticagrelor use to preserve AstraZeneca UK jobs [18].

Disclosure of financial/other conflicts of interest

Dr MR Hansen has received speaking fees from Novartis outside the submitted work, owns stocks in Novo Nordisk, and is employed in Novo Nordisk from 1 February 2022. The authors have no other relevant conflicts of interest to disclose. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

PVE and RHG contributed to the conceptualization, investigation, original draft writing, and editing the draft. THL reviewed the draft. MRH performed the postponement analyses and reviewed the draft. PVE is the named guarantor of the article.

Ethics statements

Patient consent for publication: not applicable.

Additional information

Funding

The authors have no funding to report.