Statin adherence and risk of acute cardiovascular events among women: a cohort study accounting for time-dependent confounding affected by previous adherence.
Previous studies on the effect of statin adherence on cardiovascular events in the primary prevention of cardiovascular disease have adjusted for time-dependent confounding, but potentially introduced bias into their estimates as adherence and confounders were measured simultaneously. We aimed to evaluate the effect when accounting for time-dependent confounding affected by previous adherence as well as time sequence between factors.



Retrospective cohort study.



Finnish healthcare registers.



Women aged 45-64 years initiating statin use for primary prevention of cardiovascular disease in 2001-2004 (n=42 807).



Acute cardiovascular event defined as a composite of acute coronary syndrome and acute ischaemic stroke was our primary outcome. Low-energy fractures were used as a negative control outcome to evaluate the healthy-adherer effect.



During the 3-year follow-up, 474 women experienced the primary outcome event and 557 suffered a low-energy fracture. The causal HR estimated with marginal structural model for acute cardiovascular events for all the women who remained adherent (proportion of days covered ≥80%) to statin therapy during the previous adherence assessment year was 0.78 (95% CI: 0.65 to 0.94) when compared with everybody remaining non-adherent (proportion of days covered <80%). The result was robust against alternative model specifications. Statin adherers had a potentially reduced risk of experiencing low-energy fractures compared with non-adherers (HR 0.90, 95% CI 0.76 to 1.07).



Our study, which took into account the time dependence of adherence and confounders, as well as temporal order between these factors, is support for the concept that adherence to statins in women in primary prevention decreases the risk of acute cardiovascular events by about one-fifth in comparison to non-adherence. However, part of the observed effect of statin adherence on acute cardiovascular events may be due to the healthy-adherer effect.
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland Drug Research Doctoral Programme, University of Turku, Turku, Finland.
Piia
P
Lavikainen
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland Unit of Primary Health Care, Hospital District of Helsinki and Uusimaa, Helsinki, Finland.
Arja
A
Helin-Salmivaara
The Center of Statistics, University of Turku, Turku, Finland.
Mervi
M
Eerola
Division of Pharmaceutical Outcomes and Policy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
Gang
G
Fang
Heart Center, Kuopio University Hospital, Kuopio, Finland School of Medicine, University of Eastern Finland, Kuopio, Finland.
Juha
J
Hartikainen
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland Department of Clinical Pharmacology, Tykslab, Turku University Hospital, Turku, Finland.
Risto
R
Huupponen
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland Division of Pharmaceutical Outcomes and Policy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
Maarit Jaana
MJ
Korhonen
D002318:Cardiovascular Diseases / Q000517:prevention & control*; D050171:Dyslipidemias / Q000188:drug therapy*; D005260:Female; D005387:Finland / Q000453:epidemiology; D005500:Follow-Up Studies; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D015994:Incidence; D008875:Middle Aged; D011322:Primary Prevention; D016016:Proportional Hazards Models; D012042:Registries / Q000706:statistics & numerical data; D012189:Retrospective Studies; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome; D016387:Women's Health; D016903:Drug Monitoring
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
acute coronary syndrome; acute ischemic stroke; adherence to statins; marginal structural model; time-dependent confounding; women