An observational cohort study evaluating patient characteristics and safety outcomes in new users of ticagrelor and clopidogrel in Sweden

This extension study of the ticagrelor PASS* reported that in new users of ticagrelor or clopidogrel following a recent coronary event, ticagrelor users had an elevated risk of dyspnea, respiratory bleeding, gout, and acute renal failure vs clopidogrel users, who were older and more prevalent users of concomitant medications.

Key Takeaway

  • This Swedish observational cohort study evaluating new users of ticagrelor or clopidogrel (following a recent coronary event) reported:
    • Patients receiving clopidogrel treatment were older and had a higher prevalence of concomitant medication use vs ticagrelor users
    • Elevated risk of dyspnea in current ticagrelor users vs clopidogrel users
    • Elevated risk of respiratory bleeding (mainly epistaxis) with current and recent use of ticagrelor
    • Higher risk of gout and acute renal failure in current ticagrelor users vs clopidogrel users (in adjusted analyses)

Why This Matters

  • Improved knowledge of the ticagrelor patient population and its comparison with other antiplatelet agents, would be helpful in clinical practice.
  • This observational cohort study (an extension of the original PASS* study) evaluated patient characteristics, comorbidities, concomitant medication use, and incidences of selected safety outcomes in patients receiving ticagrelor or clopidogrel treatment for the first time following a recent coronary event.
    • Prescribing patterns of ticagrelor and clopidogrel may have changed since the PASS* study
    • This study used data from Swedish national registers, encompassing the total population, and mirrored actual clinical use of the drugs

Study Design

  • Data sources (Swedish national registers): Prescribed Drug Register; National Patient Register; and Total Population Register
  • Study cohort (restricted to patients with a recent coronary event-related hospital contact): P2Y12 receptor antagonist-naïve incident clopidogrel and ticagrelor users (included at index date; age = 20–84 years; study period = June 1, 2011–December 31, 2013; excluded patients = prasugrel users [low numbers]/immigration within 6 months of index date)
  • Exposure (study medication use classification [person-time contribution by patients]): (1) “Current use” — while being treated; (2) “recent use” — from 31 days after treatment up to a maximum of 90 days; and (3) “past use” —end of recent use category until end of follow-up
  • Safety outcomes: Bleeding (intracranial, gastrointestinal, respiratory, other); pacemaker insertion; bradyarrhythmias; cardiac arrest; heart failure; acute renal failure; acute liver injury; dyspnea; syncope; and gout

Key Results

  • Patient characteristics: N = 45,987 (men = 71%; mean age = 68 years; clopidogrel cohort: n = 30,492 [69% men; mean age = 69 years]; ticagrelor cohort: n =15, 607 [73% men; mean age = 66 years]; 112 patients contributed to both cohorts)
    • Most common comorbidities and interventions related to indication included acute coronary syndrome (ACS [93%]), myocardial infarction (MI [76%]), and percutaneous coronary intervention (PCI [69%])
      • Clopidogrel vs ticagrelor users: Lower prevalence of previous MI, ACS, and PCI; comorbidities corresponding to outcomes —higher prevalence of heart failure; Charlson comorbidities —higher prevalence of cerebrovascular disease
    • Concomitant medications (clopidogrel vs ticagrelor cohort = 51%–62% vs 39%–44%): Antithrombotic agents were used most commonly (56% patients); while, others included beta-blocking agents, agents acting on renin–angiotensin system, and lipid-modifying agents
  • Crude incidences of safety outcomes (per 1000 person-years):
    • Observed incidences of bleeding in current users of either drug were numerically higher for gastrointestinal and respiratory bleeding vs intracranial and other bleeding
      • Respiratory bleeding (ticagrelor vs clopidogrel): 24.6 (95% confidence interval [CI]: 22.1–27.4) vs 14.4 (95% CI: 13.1–15.8). Epistaxis was main type of respiratory bleeding for both drugs (83%–93% of cases depending on drug and type of use)
    • Dyspnea (current ticagrelor vs current clopidogrel use): 25.9 (95% CI: 23.3–28.7) vs 16.8 (95% CI: 15.4–18.4)
    • Heart failure: Current use — ticagrelor = 27.5 (95% CI: 24.7–30.4), clopidogrel = 25.6 (95% CI: 23.7–27.5); past use — ticagrelor = 8.5 (95% CI: 6.8–10.5), clopidogrel = 11.2 (95% CI: 10.0–12.4)
    • Clopidogrel: Incidences of all outcomes except pacemaker insertion, acute liver injury, and gout displayed a declining pattern when moving from current to recent to past use
    • Ticagrelor: All outcomes except other bleeding, pacemaker insertion, acute liver injury, and gout demonstrated a declining incidence pattern moving from current to recent to past use
  • Survival analysis of safety outcomes (ticagrelor vs clopidogrel): Current use — statistically significant increased risk of respiratory bleeding, dyspnea, acute renal failure, and gout with ticagrelor; recent use — significantly increased risks of gastrointestinal and respiratory bleeding with ticagrelor; past use — no significant differences in risks between two groups


  • Key limitations included: (1) Diagnoses covered only hospital care (primary care not included); (2) differences between study cohorts (ticagrelor [new drug] vs clopidogrel [established drug]) may have affected the results; (3) exact date of treatment discontinuation and adherence was not known; (4) treatment episodes continuing beyond end of follow-up were cut short; and (5) residual confounding may have occurred in adjusted analyses

* PASS: Post-authorization safety study of ticagrelor initiated in 2011

    Linder M, Andersen M. Patient characteristics and safety outcomes in new users of ticagrelor and clopidogrel-An observational cohort study in Sweden. Pharmacoepidemiol Drug Saf. 2022;31(2):235–246. doi: 10.1002/pds.5387. PMID: 34802175.