Recurrence and Mortality in Young Women With Myocardial Infarction or Ischemic Stroke: Long-term Follow-up of the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) Study | Acute Coronary Syndromes | JAMA Network
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Figure.  Kaplan-Meier Curves for Overall Mortality
Kaplan-Meier Curves for Overall Mortality

IS indicates ischemic stroke; MI, myocardial infarction.

Table.  Incidence Rates and Hazard Ratios for Cardiovascular Events
Incidence Rates and Hazard Ratios for Cardiovascular Events
1.
Go  AS, Mozaffarian  D, Roger  VL,  et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee.  Heart disease and stroke statistics--2014 update: a report from the American Heart Association.  Circulation. 2014;129(3):e28-e292.PubMedGoogle ScholarCrossref
2.
Rutten-Jacobs  LC, Arntz  RM, Maaijwee  NA,  et al.  Long-term mortality after stroke among adults aged 18 to 50 years.  JAMA. 2013;309(11):1136-1144.PubMedGoogle ScholarCrossref
3.
Kemmeren  JM, Tanis  BC, van den Bosch  MA,  et al.  Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study: oral contraceptives and the risk of ischemic stroke.  Stroke. 2002;33(5):1202-1208.PubMedGoogle ScholarCrossref
4.
Tanis  BC, van den Bosch  MA, Kemmeren  JM,  et al.  Oral contraceptives and the risk of myocardial infarction.  N Engl J Med. 2001;345(25):1787-1793.PubMedGoogle ScholarCrossref
5.
Cole  JH, Miller  JI  III, Sperling  LS, Weintraub  WS.  Long-term follow-up of coronary artery disease presenting in young adults.  J Am Coll Cardiol. 2003;41(4):521-528.PubMedGoogle ScholarCrossref
6.
Putaala  J, Haapaniemi  E, Metso  AJ,  et al.  Recurrent ischemic events in young adults after first-ever ischemic stroke.  Ann Neurol. 2010;68(5):661-671.PubMedGoogle ScholarCrossref
Research Letter
January 2016

Recurrence and Mortality in Young Women With Myocardial Infarction or Ischemic Stroke: Long-term Follow-up of the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) Study

Author Affiliations
  • 1Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
  • 2Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
  • 3Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany
  • 4Brain Center Rudolph Magnus, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, the Netherlands
  • 5Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
  • 6Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, the Netherlands
JAMA Intern Med. 2016;176(1):134-136. doi:10.1001/jamainternmed.2015.6523

Rates of death in the acute phase of cardiovascular events have decreased, but disease burden remains high in the increasing number of survivors.1 This finding is particularly important for those affected at a young age.2 Nevertheless, little information is available on the long-term outcome of young patients who survived a cardiovascular event, especially women. Single disease cohorts have suggested that the risk of cardiovascular disease is driven by recurrence of the index event, but, to our knowledge, this has never been investigated in a single study with multiple index groups. We determined the long-term mortality and subtype-specific morbidity in young women surviving myocardial infarction (MI) or ischemic stroke (IS) compared with a control group.

Methods

A cohort was formed on the basis of the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study, which included consenting women aged 18 to 50 years who survived a first MI or IS from January 1, 1995, through December 31, 1998.3,4 Women with no history of arterial thrombosis were recruited as controls. The study was approved by the ethics committees of the participating hospitals. All patients provided written informed consent. Women were followed up to December 31, 2012, by linkage to the Dutch Registry of death certificates and to the Dutch Hospital Data register (Central Bureau of Statistics) for causes of death and hospital admissions. Data analysis was performed from December 1, 2013, through September 30, 2014. Incidence rates (IRs) and their ratios were calculated for mortality and the first reoccurrence of any acute major cardiovascular event during follow-up. Adjusted hazard ratios (HRs) obtained from Cox proportional hazards regression models were used for comparison with the controls.

Results

A total of 226 women with MI, 160 with IS, and 782 controls (mean age, 42.4, 40.0, and 48.4 years, respectively) were followed up for a median of 18.7 years (interquartile range, 17.5-20.5 years). Mortality rates were 3.7 (95% CI, 2.5-5.4) times higher in patients with MI (IR, 8.8 per 1000 person-years; 95% CI, 6.2-12.3) and 1.8 (95% CI, 1.0-3.5) times higher in patients with IS (IR, 4.4 per 1000 person-years; 95% CI, 2.4-7.6) than in controls (IR, 2.4 per 1000 person-years; 95% CI, 1.7-3.4). This elevated mortality persisted over time (Figure) and was mainly supported by a high rate of deaths from acute vascular events: vascular mortality rate, 3.5 per 1000 person-years (95% CI, 1.9-5.9) in patients with MI, 2.1 per 1000 person-years (95%, 0.8-4.5) in patients with IS, and 0.3 per 1000 person-years (95% CI, 0.1-0.7) in controls.

When counting both fatal and nonfatal cardiovascular events, the IR was highest in patients with IS at 14.1 per 1000 person-years (95% CI, 9.9-19.4), corresponding to an HR of 12.9 (95% CI, 6.7-25.0) compared with controls (Table). The rate was 12.1 per 1000 person-years (95% CI, 8.7-16.2) in patients with MI, with an HR of 9.8 (95% CI, 5.0-19.4) in contrast with controls.

In patients with MI, the rate of cardiac events was 10.1 per 1000 person-years (95% CI, 7.5-13.8) whereas the rate of cerebral events was 1.9 per 1000 person-years (95% CI, 0.8-3.8). In patients with IS, the reverse picture was observed, with a rate of cerebral events of 11.1 per 1000 person-years (95% CI, 7.5-15.9), whereas the risk of cardiac events was 2.7 per 1000 person-years (95% CI, 1.2-5.4).

Discussion

Young women who survived a cardiovascular event have a high long-term mortality and morbidity when compared with the general population. The recurrence pattern is true to type (ie, the recurrence rate for cerebrovascular disease is highest in patients with IS whereas the risk of cardiac events is highest in patients with MI). This finding is supported by studies5,6 that investigated IS and MI separately.

A limitation of this study is the possibility of survival bias owing to the case-control nature of the study cohort, and therefore absolute risks for the period shortly after the first event may have been underestimated. Moreover, procedures and risk factors change over time, which reduces the generalizability of our results, a problem of all long-term follow-up studies. Our findings provide direct insight into the consequences of cardiovascular diseases in young women, which persist for decades after the initial event, stressing the importance of lifelong prevention strategies.

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Article Information

Corresponding Author: Frits R. Rosendaal, MD, PhD, Department of Clinical Epidemiology, Leiden University Medical Center, Bldg C, Floor 7, PO Box 9600, 2300 RC Leiden, the Netherlands (f.r.rosendaal@lumc.nl).

Published Online: November 23, 2015. doi:10.1001/jamainternmed.2015.6523.

Author Contributions: Drs Maino and Siegerink had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Maino, Siegerink, Algra, Rosendaal.

Acquisition, analysis, or interpretation of data: Maino, Siegerink, Algra, Peyvandi.

Drafting of the manuscript: Maino, Siegerink.

Critical revision of the manuscript for important intellectual content: Siegerink, Algra, Peyvandi, Rosendaal.

Statistical analysis: Maino, Siegerink.

Obtained funding: Maino, Siegerink, Rosendaal.

Administrative, technical, or material support: Maino, Peyvandi.

Study supervision: Siegerink, Algra, Rosendaal.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by grant 3216/28-3-13/DM from the noncommercial Den Dulk Moermans Fonds. The study was also financially supported by the Fondazione Angelo Bianchi Bonomi, Milan, Italy (Dr Maino).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Previous Presentation: This work was presented at the 2015 meeting of the International Society of Thrombosis and Hemostasis; June 23, 2015; Toronto, Ontario, Canada.

References
1.
Go  AS, Mozaffarian  D, Roger  VL,  et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee.  Heart disease and stroke statistics--2014 update: a report from the American Heart Association.  Circulation. 2014;129(3):e28-e292.PubMedGoogle ScholarCrossref
2.
Rutten-Jacobs  LC, Arntz  RM, Maaijwee  NA,  et al.  Long-term mortality after stroke among adults aged 18 to 50 years.  JAMA. 2013;309(11):1136-1144.PubMedGoogle ScholarCrossref
3.
Kemmeren  JM, Tanis  BC, van den Bosch  MA,  et al.  Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study: oral contraceptives and the risk of ischemic stroke.  Stroke. 2002;33(5):1202-1208.PubMedGoogle ScholarCrossref
4.
Tanis  BC, van den Bosch  MA, Kemmeren  JM,  et al.  Oral contraceptives and the risk of myocardial infarction.  N Engl J Med. 2001;345(25):1787-1793.PubMedGoogle ScholarCrossref
5.
Cole  JH, Miller  JI  III, Sperling  LS, Weintraub  WS.  Long-term follow-up of coronary artery disease presenting in young adults.  J Am Coll Cardiol. 2003;41(4):521-528.PubMedGoogle ScholarCrossref
6.
Putaala  J, Haapaniemi  E, Metso  AJ,  et al.  Recurrent ischemic events in young adults after first-ever ischemic stroke.  Ann Neurol. 2010;68(5):661-671.PubMedGoogle ScholarCrossref
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