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. 2021 Feb 16;143(7):685-695.
doi: 10.1161/CIRCULATIONAHA.120.052339. Epub 2021 Feb 15.

Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials: Insights From the TIMI trials

Emily S Lau  1   2 , Eugene Braunwald  3   2 , David A Morrow  3   2 , Robert P Giugliano  3   2 , Elliott M Antman  3   2 , C Michael Gibson, Benjamin M Scirica  3   2 , Erin A Bohula  3   2 , Stephen D Wiviott  3   2 , Deepak L Bhatt  4   2 , Marc P Bonaca  5 , Christopher P Cannon  4   2 , KyungAh Im  3   2 , Jianping Guo  3   2 , Marc S Sabatine  3   2 , Michelle L O'Donoghue  3   2
Affiliations

Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials: Insights From the TIMI trials

Emily S Lau et al. Circulation. .

Abstract

Background: Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug or withdraw consent once enrolled in a clinical trial is unknown.

Methods: Eleven phase 3/4 TIMI (Thrombolysis in Myocardial Infarction) trials were included (135 879 men and 51 812 women [28%]). The association between sex and premature study drug discontinuation and withdrawal of consent were examined by multivariable logistic regression after adjusting for potential confounders in each individual trial and combining the individual point estimates in random effects models.

Results: After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation (adjusted odds ratio [ORadj], 1.22 [95% CI, 1.16-1.28]; P<0.001) compared with men. Qualitatively consistent results were observed for women versus men in the placebo arms (ORadj, 1.20 [95% CI, 1.13-1.27]) and active therapy arms (ORadj, 1.23 [95% CI, 1.17-1.30)]; there was some evidence for regional heterogeneity (P interaction <0.001). Of those who stopped study drug prematurely, a similar proportion of men and women in the active arm stopped because of an adverse event (36% for both; P=0.60). Women were also more likely to withdraw consent compared with men (ORadj, 1.26 [95% CI, 1.17-1.36]; P<0.001).

Conclusions: Women were more likely than men to prematurely discontinue study drug and withdraw consent across cardiovascular outcome trials. Premature study drug discontinuation was not explained by baseline differences by sex or a higher proportion of adverse events. Future trials should better capture reasons for drug discontinuation and withdrawal of consent to understand barriers to continued study drug use and clinical trial participation, particularly among women.

Keywords: cardiovascular drugs; clinical trial; women.

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Figures

Figure 1.
Figure 1.. Premature Study Drug Discontinuation in Women vs Men.
Size of data marker is weighted based on the inverse variance. TRITON-TIMI 38 = Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38; TRA2P-TIMI 50 = Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50; ATLAS ACS2-TIMI 51 = Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51; PEGASUS-TIMI 54 = Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on Background of Aspirin-Thrombolysis in Myocardial Infarction 54; IMPROVE-IT (TIMI 40) = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; SOLID-TIMI 52 = Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52; FOURIER (TIMI 59) = Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; MERLIN-TIMI 36 = Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes- Thrombolysis in Myocardial Infarction 36; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus- Thrombolysis in Myocardial Infarction 53; DECLARE-TIMI 58 = Dapagliflozin Effect on Cardiovascular Events- Thrombolysis in Myocardial Infarction 58; CAMELLIA-TIMI 61 = Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients- Thrombolysis in Myocardial Infarction 61. Please see Table 1 legend for additional abbreviations.
Figure 2.
Figure 2.. Adjusted odds of study drug discontinuation in women versus men stratified by subgroups of interest.
n and (%) represent the number of subjects with study drug discontinuation and corresponding percentages, Abbreviations: BMI = body mass index, eGFR = estimated glomerular filtration rate, MI = myocardial infarction
Figure 3.
Figure 3.. Withdrawal of Consent in Women vs Men.
Size of data marker is weighted based on the inverse variance. Abbreviations as in Figure 1. Please see Table 1 legend for additional abbreviations.
See this image and copyright information in PMC

Comment in

  • Adherence to Study Drugs: A Matter of Sex?
    Sederholm Lawesson S, Swahn E, Alfredsson J. Sederholm Lawesson S, et al. Circulation. 2021 Feb 16;143(7):696-698. doi: 10.1161/CIRCULATIONAHA.121.053493. Epub 2021 Feb 15. Circulation. 2021. PMID: 33587664 No abstract available.

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