OBJECTIVES:The extent of triptan use among users of combined hormonal contraceptives (CHC) is unknown. Likewise, it is unclear whether triptan use influences the risk of stroke in CHC users. In a Danish population of CHC users, we examined the prevalence of triptan use and assessed its impact on stroke risk. STUDY DESIGN:In this historical cohort study based on registries covering the Danish female population aged 18-49 years 2004-2021 we investigated incidence rate ratios (IRR) and incidence rate differences (IRD) of ischemic (IS) and hemorrhagic (ICH) stroke in users of CHCs who had been prescribed triptans compared with those without triptan use. Poisson regression models adjusting for age, ethnicity, education, calendar year and risk factors were applied. RESULTS:Among 1711,757 women, 982,962 (57%) were CHC users, contributing 4446,000 person-years of CHC use. Of these, 98,399 (10%) had used triptans, contributing 325,000 person-years. CHC users with triptan prescriptions had an increased risk of IS compared to users without prescriptions (IRR 1.60; 95% CI 1.33,1.92); IRD range by age group 2-42/100,000 person-years). Stroke risk was independent of triptan prescription frequency and ethinylestradiol dose. Compared with women who use neither CHCs, other hormonal contraceptives, nor triptans, CHC users with triptan prescriptions had an increased risk of IS (IRR 2.61; 95% CI: 2.21-3.08). Risk was not increased for ICH. CONCLUSIONS:Among approximately one million Danish CHC users, 10% had been prescribed triptans. In this population the risk of IS was increased 1.60-fold compared with those without triptan use. Triptan use constitutes a risk factor for IS in CHC users. Although the absolute risk is generally low, it is highest among the oldest users. IMPLICATIONS:Among approximately one million Danish CHC users, 10% had been prescribed triptans, and in this group the risk of ischemic stroke was 1.60 times higher. Among CHC users with migraine, triptan use should be regarded as a risk factor for ischemic stroke and taken into account when considering CHCs as a contraceptive option.

OBJECTIVE:We studied the risk of ischemic (IS) and hemorrhagic stroke (ICH) in users of progestogen-only contraceptives (POCs): levonorgestrel-releasing intrauterine device (LNG-IUD), progestogen-only pill (POP), implant and injection. STUDY DESIGN:In this nationwide cohort study using Danish registry data for all women aged 18-49 years, 2004-2021, we estimated incidence rate ratios (IRRs) for IS and ICH associated with POC use. Comparisons were made with non-use of hormonal contraception and with combined hormonal contraceptives (CHC) with ethinylestradiol containing equivalent progestogens. Poisson regression models were adjusted for age, ethnicity, education, calendar year, and risk factors. RESULTS:A total of 1,734,905 non-pregnant women contributed 16,854,953 person-years of follow-up. The most frequently used POCs were LNG-IUD (1,720,931 person-years), followed by desogestrel-only pills (255,404), norethisterone-only pills (104,261), etonogestrel implants (61,756), and medroxyprogesterone injections (27,469). CHCs with ethinylestradiol accounted for 4,431,841 person-years. Compared with non-use of hormonal contraception, no POC type was associated with increased adjusted IRRs for IS or ICH. Compared with CHCs containing desogestrel or levonorgestrel in addition to ethinylestradiol, adjusted IRRs for IS were significantly lower for desogestrel-only pills (IRR 0.56, 95%CI 0.38, 0.82) and LNG-IUD (IRR 0.44, 95%CI 0.36, 0.53). IRRs for ICH were not significantly changed: LNG-IUD 0.85 (95%CI 0.37, 1,92); desogestrel-only pills 0.98 (95%CI 0.44, 2,20). CONCLUSION:POCs were not associated with increased stroke risk. Relative to CHCs with ethinylestradiol, POCs were linked to approximately half the risk of IS. However, the absolute number of strokes avoided by choosing POCs over CHCs with ethinylestradiol is small and, for most women-particularly those under 40 years-unlikely to be clinically detectable. IMPLICATIONS:POCs-including POPs, implants, injections, and LNG-IUDs-were not associated with an increased risk of either IS or ICH and support their use as appropriate alternatives to CHCs with ethinylestradiol for women in whom stroke risk is an important clinical consideration.

BACKGROUND: The combined hormonal contraceptive (CHC) with ethinylestradiol and progestins is the most widely used contraceptive method among young women and is used by millions worldwide. However, uncertainties exist about the risk of ischemic stroke associated with the use of CHCs with low-dose ethinylestradiol (<50-g ethinylestradiol) and with the newest fourth-generation progestins that have only been sparsely investigated for the risk of ischemic stroke. METHODS: In this cohort study based on Danish registries covering the entire Danish female population aged 18 to 49 years from 2004 to 2021, we investigated incidence rate ratios (IRRs) of ischemic stroke using CHCs compared with nonuse of hormonal contraceptives. Analyses focused on comparing CHCs based on ethinylestradiol content (30-40- versus <= 20-mu g ethinylestradiol), progestin generation (second, third, and fourth) in CHCs, and route of administration (monophasic versus sequential). Poisson regression models adjusting for age, education, ethnicity, calendar year, and medication used for risk factors were utilized. RESULTS: In total, 1 711 757 nonpregnant women contributed 14 697 788 person-years to the investigation. For users of CHCs containing <50-g ethinylestradiol, the adjusted IRR was increased by 1.77 (95% CI, 1.62-1.93) compared with nonusers of hormonal contraceptives. IRR did not differ between CHCs with 30- to 40- and <= 20-mu g ethinylestradiol. Adjusted incidence rate difference between CHC users and nonusers of hormonal contraceptives ranged from 1 in 100 000 women per year in 18 to 24 years of age to 24 in 100 000 women per year in >= 45 years of age. Incidence rate in users of fourth-generation CHCs was 30% lower than that of second-generation CHCs adjusted IRR (0.70 [95% CI, 0.50-0.98]). IRR for users of third-generation CHCs did not differ significantly from that of second-generation users adjusted IRR (1.14 [95% CI, 0.97-1.35]). CONCLUSIONS: Use of CHCs was associated with a 1.77 higher IRR of ischemic stroke. IRR did not relate to ethinylestradiol content in users of CHCs with <50-g ethinylestradiol. IRR was 30% lower in users of fourth-generation than in users of second-generation CHCs.

BACKGROUND:The commonly used combined hormonal contraceptives with progestins and ethinylestradiol are associated with an increased risk of ischemic stroke (IS). Progestin-only preparations, including levonorgestrel-releasing intrauterine devices (LG-IUDs), are not associated with an increased risk, and in smaller studies, the risk is even reduced. The risk of intracerebral hemorrhage (ICH) has never been investigated. We studied the risk of IS and ICH in women using LG-IUDs compared with women not using hormonal contraceptives.METHODS:In this Danish historical cohort study (2004-2021), we followed nonpregnant women (18-49 years) registering incident IS and ICH in relation to use of LG-IUDs/nonuse of hormonal contraceptives utilizing Danish high-quality registries with nationwide coverage. Poisson regression models adjusting for age, ethnicity, education, calendar year, and medication use for risk factors were applied.RESULTS:A total of 1 681 611 nonpregnant women contributed 11 971 745 person-years (py) of observation. Mean age at inclusion was 30.0 years; mean length of follow-up was 7.1 years; 2916 women (24.4 per 100 000 py) had IS; 367 (3.1 per 100 000 py) had ICH. Of these, 364 784 were users of LG-IUD contributing 1 720 311 py to the investigation; mean age at start of usage was 34.6 years. Nonusers of hormonal contraceptives contributed 10 251 434 py; mean age at inclusion was 30.0 years. The incidence rate of IS/ICH among LG-IUD users was 19.2/3.0 and among nonusers, it was 25.2/3.1 per 100 000 py. After adjustment, incidence rate ratio for IS was 0.78 (CI, 0.70-0.88), and for ICH it was 0.94 (CI, 0.69-1.28).CONCLUSIONS:The use of LG-IUD was associated with a 22% lower incidence rate of IS without raising the incidence rate of ICH. The finding raises the question of whether levonorgestrel, in addition to its contraceptive properties, could have the potential to prevent IS.

OBJECTIVE:Uncertainty exists for the absolute risk of ischemic and hemorrhagic stroke in users of oral contraceptives (OCs). Estimates greatly vary between countries. In Denmark, absolute risk of ischemic stroke (IS) is estimated to be 21 per 100,000 person-years. Risk of cerebral hemorrhage (CH) is unknown. Using the Danish Stroke Registry, we investigated absolute risk of IS and CH in users of OC.MATERIAL AND METHODS:For the Danish female population aged 15-49 years during 2003-2011, we obtained information on hospital admission for IS and CH and current use of OC from Danish nationwide registries. We defined current use of OC as redeeming at least two OC prescriptions within the previous year.RESULTS:The Danish female population years 2003-2011 consisted mean of 1,246,142 women per year. Of these, 29.6% were OC users. In the study period, OC users had 291 IS and 14 CH. Absolute risk of IS in OC users was 8.8 per 100,000 person-years and of CH it was 0.4 per 100,000 person-years.CONCLUSIONS:In OC users, absolute risk of IS was 8.8 per 100,000 person-years. This is more than half that of the risk previously assumed in Denmark. Risk of CH in OC users was very low and 0.4 per 100,000 person-years.

Introduction Symptoms of occult brain cancer may mimic stroke. Misdiagnosis may lead to improper treatment and delayed diagnosis. We characterised strokes associated with occult primary brain cancer and determined risk that ischaemic and haemorrhagic strokes are associated with occult primary brain cancer. Patients and methods All patients with incident stroke in Denmark 2003–2015 were identified through the Danish Stroke Registry (n = 85,893) and matched 1:10 on age and sex to the Danish background population without a stroke history (n = 858,740). This cohort was linked to the Danish Cancer Registry and prevalence of occult primary brain cancer defined as the event of previously unknown primary brain cancer during a one-year follow-up was estimated. We used Cox regression models to study risk of occult primary brain cancer in comparison to the background population. Results Of 77,484 patients with ischaemic strokes, 39 (1 in 2000) were associated with primary brain cancer; of 8409 with haemorrhagic strokes, it was 126 (1 in 66). In the background cohort, 205 (1 in 4000) had occult primary brain cancer. The multivariate stroke risk factor analysis showed that patients with occult primary brain cancer differed significantly from those without occult primary brain cancer indicating they might have stroke mimics rather than true strokes. Discussion and conclusions: Strokes associated with occult primary brain cancer tend to be stroke mimics rather than true strokes. Primary brain cancer is rare in patients with ischaemic stroke (1 in 2000); risk that misdiagnosis results in maltreatment is, therefore, very low. Occult primary brain cancers are mainly found among patients with haemorrhagic stroke; they are not uncommon (1 in 66) and should always be kept in mind.

Background: Lung cancer and stroke share smoking as a major cause of disease. We investigated prevalence and risk of occult lung cancer with manifestation during the first year after stroke. Methods: All patients >40 years of age with incident stroke in Denmark 2003-2015 were identified through the Danish Stroke Registry (n=85,893) and matched 1:10 on age and sex to the Danish background population without a history of stroke (n=858,740). Linking data to the Danish Cancer Registry we determined prevalence of occult primary lung cancer defined as the event of previously unknown lung cancer during a one-year follow-up in the stroke and the background population. Cox regression models with adjustments for demographics, co-morbidities and stroke risk factors were used to study risk compared to the background population. Results: Prevalence (per 1000 person-years) of occult lung cancer in the stroke cohort was 5.3; in the background cohort 2.6. Prevalence separately for current smokers (n=26,055) was 9.6; ex-smokers (n=20,035) 6.5; never-smokers (n=27,268) 1.4. Risk of occult lung cancer (adjusted) was increased HR 1.95 in the stroke population. In the stroke population adjusting for stroke risk factors age (HR 1.24 per 10 years) and smoking (HR 7.1 in current smokers; HR 1.6 in ex-smokers) were the only significant risk factors for occult lung cancer. Conclusions: Occult lung cancer is rarely found in stroke patients who have never smoked. It is not uncommon in smokers in whom 1% of current smokers had occult lung cancer that became manifest within the first year after stroke.

Objectives Stroke is associated with a higher risk of occult cancer. We studied the types of occult cancer most often associated with stroke. Materials and Methods All patients with incident stroke in Denmark 2003-2015 were identified through the Danish Stroke Registry (n = 85 893) and matched 1:10 on age and sex to the Danish background population without history of stroke (n = 858 740). Linking data to the Danish Cancer Registry, we determined the prevalence of occult cancer in stroke defined as the event of previously unknown cancer during a one-year follow-up in the stroke and the background population. We stratified cancers into the 15 most common cancers and into cancers related to and not related to smoking. Results Prevalence (per 1000 person-years; stroke/background population) of smoking-related occult cancers (lung, colon, bladder rectum, pancreas, kidney, stomach, and head and neck) was 13.3/8.1 (P < .01) and of cancers not related to smoking (prostate, breast, melanoma, non-Hodgkin lymphoma, ovary, endometrial) it was 6.6/6.2 (P > .05). Among men with stroke prostate (5.8), lung (5.7), and colon cancers (2.9) were most frequent; among women, it was lung (4.7), breast(3.5), and colon cancer(2.8). Among men in the background population, prostate(5.4), lung (3.0), and colon cancers (2.1) were most frequent. Among women, it was breast (3.7), lung(2.1), and colon cancers (1.9). Conclusion Stroke patients' increased risk of occult cancer was predominantly for smoking-related cancers while there was no higher risk for the most frequent cancers unrelated to smoking, that is, prostate and breast cancers. Lung cancer is the dominant type of occult cancer in stroke.

Goals: It is unclear whether social inequality exists for mortality after stroke. Results of studies on the relation between socioeconomic position (SEP) and mortality after stroke have been inconsistent and inconclusive. Material and Methods: We studied the association between SEP expressed by income and the risk of death after stroke by merging data on incident stroke from Danish registries with nationwide coverage. We identified all incident cases of stroke hospitalized in Denmark 2003-2012 (n = 60503). Patients were followed up to 9 years after stroke (median 2.6 years). Adjusting for age and sex we studied all-cause death and cause-specific death by stroke, cardiac disease, cancer, and other diseases certified by death records and stratified by income. Results: Of the patients 20,953 (34.6%) had died within follow-up: Death by stroke 8018 (13.2%); cardiac disease 4250 (7.0%); cancer 3060 (5.0%); other diseases 5625 (9.2%). Long-term mortality rates were inversely related to income for all causes of death. The difference in mortality between the lowest and the highest income group at 5 years after stroke was 15.5% (relative) and 5.7% (absolute). Differences in short-term mortality (1-month to 1-year) between income groups were small and clinically insignificant. Conclusions: Social inequality in mortality after stroke expressed by income was pronounced for long-term mortality while not for short-term mortality. It seems that social inequality is expressed in a greater risk among stroke patients with low income for the advent of new diseases subsequently leading to death rather than in their ability to survive the incident stroke.

OBJECTIVES:Cancer is associated with higher risk of stroke. Whether this translates into higher risk of cancer in stroke of an extent calling for cancer screening in stroke is unclear. We investigated prevalence and risk of occult cancer in stroke compared to the background population without history of stroke.MATERIALS AND METHODS:All patients >40 years of age with incident stroke in Denmark 2003-2015 were identified through the Danish Stroke Registry (n = 85 893) and matched 1:10 on age and sex to the Danish background population without history of stroke (n = 858 740). Linking data to the Danish Cancer Registry, we determined prevalence of occult cancer in stroke defined as the event of previously unknown cancer during a 1-year follow-up in the stroke and in the background population. Cox regression models were used to study risk in comparison to the background population.RESULTS:Prevalence (per 1000) of occult cancer in the stroke/background cohorts was 25.0/15.8 in women and 29.8/20.4 in men. Prevalence was dependent on age and sex. Highest among stroke patients aged 70-80 years (35.6 in women, 42.4 in men); lowest in patients aged 40-50 years (8.3 in women, 6.8 in men). Stroke was associated with an overall 54% higher risk of occult cancer but risk increased significantly with smoking, hazard ratio (HR) 1.47, age HR 1.27 per 10 years, male sex HR 1.25, and diabetes HR 1.25.CONCLUSIONS:Prevalence and risk of occult cancer in stroke is considerable and calls for attention when designing the stroke investigation program.

OBJECTIVES:Most studies show that marriage conveys a survival advantage. Whether this is valid also for stroke patients is unclear. Results of studies have been inconsistent and conflicting.MATERIAL & METHODS:We studied 1-week and 1-month stroke case-fatality in relation to marital status (married, unmarried, divorced, and widowed) in all patients admitted to hospital for incident stroke in Denmark during 2003-2012. We used information from Danish registries on stroke merged to information on age, sex, marital status, stroke severity, stroke subtype, socioeconomic status, cardiovascular risk profile, and causes of death. We studied deaths due to the index stroke within the first week and month after stroke. Multivariate Cox regression models were applied to estimate cause-specific hazards and relative risks.RESULTS:We included 60507 patients with an incident stroke of which 51.19% were married, 9.47% were unmarried, 13.29% were divorced, and 26.05% were widowers. Death within the first week and first month was caused by stroke in 2110 (3.5%) and 3423 (5.7%) patients, respectively. Compared to married stroke patients, 1-week/1-month case-fatality (by stroke) was lower for the unmarried (HR (hazard ratio):0.69/0.74), divorced (HR:0.69/0.72), and widowed (HR:0.80/0.74) men and the unmarried (HR:0.84/0.86), divorced (HR:0.82/0.80), and widowed (HR:0.87/0.88) women with stroke.CONCLUSIONS:One-week and one-month case-fatality by stroke was lower among the unmarried, divorced, and widowed than among the married stroke patients. Selection by so-called mortality displacement linked to shorter life expectancy among divorced, widowed, and singles may explain our findings.

OBJECTIVES:Most studies report that marriage carries a lower risk of stroke than single living. Whether the marriage advantage is applicable with respect to all other marital status categories (unmarried, divorced, widow) remains unclear. We studied marital status and its association with incident stroke.MATERIAL AND METHODS:We included all patients > 40 years of age admitted to hospital for stroke in Denmark during 2003-2012 and compared marital status to the general Danish population (5.5 millions). Relative risks (RR) for stroke were estimated in log-linear Poisson regression models adjusting for age, sex, calendar year, income, and length of education.RESULTS:A total of 58 847 patients with incident stroke were included. Crude incidence rates of stroke (per 1000 per year) among the four marital status categories were as follows: 1.96 (married), 1.52 (unmarried), 2.36 (divorced), and 5.43 (widowed). Compared to married persons, adjusted risk of stroke was significantly increased for divorced (RR 1.23; CI 1.19-1.27) and unmarried men (RR 1.07; CI 1.03-1.11) but not for widowed men (RR 1.02; CI 0.98-1.06); risk was slightly increased for divorced women (RR 1.10; CI 1.06-1.15) while not for widowed (RR 1.0; CI 0.97-1.03) and unmarried women (RR 0.97; CI 0.97-1.03).CONCLUSIONS:Divorce was associated with higher risk of stroke, especially in men. Living in marriage or as unmarried or widower had only little or no impact on the risk of stroke.

Background and Purpose— Manifest cancer is associated with increased risk of stroke. The risk of stroke in people with occult cancer in comparison to the risk in the background population without cancer has not been investigated. Smoking is a risk factor for both cancer and stroke, but the role of smoking for the risk of stroke in cancer has not been investigated. Methods— We identified all incident cases of cancer in Denmark 2003 to 2012 (n=264.376) from the Danish Cancer Registry. Each person with cancer was matched by age, sex, and income with 10 randomly selected persons without cancer at index date (n=2.571.260). Linking data to the Danish Stroke Registry, we studied risk of ischemic/hemorrhagic stroke the year before (occult cancer) and after cancer diagnosis was established in the Danish Stroke Registry (manifest cancer) and stratified into the 15 most common cancer types related (lung, colon, bladder, rectum, pancreas, kidney, stomach, and head and neck cancer) and unrelated (non-Hodgkin lymphoma, breast, prostate, melanoma, central nervous system, ovary and endometrial) to smoking. Results— Risk of ischemic/hemorrhagic stroke was increased for both occult (relative risk, 1.75/2.00) and manifest cancers (relative risk, 1.30/1.41). For occult cancer, risk of ischemic stroke was increased for all of the smoking-related cancers, but among cancers unrelated to smoking, only lymphoma, central nervous system, and endometrial cancer were associated with increased risk of stroke; breast, prostate, melanoma, and ovarian cancers were not. For occult cancer, risk of hemorrhagic stroke was generally increased for smoking-related cancers while not for cancers unrelated to smoking. For manifest cancer, risk of ischemic and hemorrhagic stroke was generally increased for cancers related to smoking while not for cancers unrelated to smoking. Conclusions— Cancer, occult and manifest, is associated with increased risks for stroke. The increased risk is linked mainly to cancers related to smoking.