Sex-Related Disparities in Cardiovascular Outcomes Among Older Adults With Late-Onset Hypertension

Abstract

BACKGROUND:

It is unclear whether sex-based differences in cardiovascular outcomes exist in late-onset hypertension.

METHODS:

This is a population-based cohort study in Ontario, Canada of 266 273 adults, aged ≥66 years with newly diagnosed hypertension. We determined the incidence of the primary composite cardiovascular outcome (myocardial infarction, stroke, and congestive heart failure), all-cause mortality, and cardiovascular death by sex using Cox proportional hazard models adjusted for demographic factors and comorbidities.

RESULTS:

The mean age of the total cohort was 74 years, and 135 531 (51%) were female. Over a median follow-up of 6.6 (4.7–9.0) years, females experienced a lower crude incidence rate (per 1000 person-years) than males for the primary composite cardiovascular outcome (287.3 versus 311.7), death (238.4 versus 251.4), and cardiovascular death (395.7 versus 439.6), P<0.001. The risk of primary composite cardiovascular outcome was lower among females (adjusted hazard ratio, 0.75 [95% CI, 0.73–0.76]; P<0.001) than in males. This was consistent after adjusting for the competing risk of all-cause death with a subdistributional hazard ratio, 0.88 ([95% CI, 0.86–0.91]; P<0.001).

CONCLUSIONS:

Females had a lower risk of cardiovascular outcomes compared with males within a population characterized by advanced age and new hypertension. Our results highlight that the severity of outcomes is influenced by sex in relation to the age at which hypertension is diagnosed. Further studies are required to identify sex-specific variations in the diagnosis and management of late-onset hypertension due to its high incidence in this group.

NOVELTY AND RELEVANCE.

What Is New?

We examined sex differences in important clinical outcomes of older people with late-onset hypertension.

What Is Relevant?

In the population, 25% of older adults developed hypertension.

Females were 25% less likely to experience a composite cardiovascular outcome compared with males.

This finding was consistent after adjusting for the competing risk of all-cause death.

Clinical/Pathophysiological Implications

Future studies should identify potential sex-specific variations in the diagnosis and management of hypertension. This approach will promote targeted and personalized approaches to hypertension management and optimize clinical outcomes in both sexes.

Cardiovascular disease is a leading cause of mortality among females worldwide.¹ As hypertension is the most important modifiable risk factor for cardiovascular disease, understanding sex-based differences in hypertension-related risk is key for improving females’ cardiovascular health and outcomes.^2,3 Despite its common prevalence in females and well-established biological differences by sex, females are underrepresented in contemporary hypertension trials, which are thus unable to systematically explore sex disparities in outcomes.^2,4,5

Complications of hypertension such as stroke and heart failure are sex dependent, but these associations are largely based on studies in younger populations with prevalent hypertension. Early studies intermixed patients with new-onset (incident) hypertension with existing (prevalent) patients with hypertension with introducing a possible bias in estimates of the association between sex and cardiovascular outcomes.^6–9 Although these findings suggest that females may be at higher risk of hypertensive complications, the sex-based differences in mortality limit the validity of these results in the absence of adjusting for death as a competing risk. Furthermore, as a large portion of incident hypertension occurs in older adults (≥65 years), the generalizability of these findings to the older population is unclear.

New-onset hypertension is 4-fold higher among postmenopausal females than premenopausal females, whereas the incidence in age-matched males is only 3-fold, potentially putting older females at greatest risk for cardiovascular morbidity and mortality.^10,11 Despite this, limited literature exists regarding the outcomes in females of advanced age with late-onset hypertension. Paradoxically, observational data find that there is a lower risk of mortality in incident hypertension in older adults compared with younger adults, although data were largely restricted to male participants.⁶ Older adults are underrepresented in hypertension studies and in combination with predominant male cohorts, there is a paucity of evidence on the sex differences in late-onset hypertension. To further clarify the cardiovascular consequences of hypertension in females and to encompass the later onset of hypertension in postmenopausal females, we examine the cardiovascular outcomes in females of advanced age with new-onset hypertension in a contemporary cohort.

METHODS

The deidentified, patient-level data used in this study will not be made publicly available.

Study Design and Setting

We conducted a population-based, retrospective cohort study of older adults (≥66 years) who were newly diagnosed with hypertension in Ontario, Canada. This study spanned from January 1, 2010, to December 31, 2021, using linked databases held at the Institute for Clinical Evaluative Sciences (ices.on.ca), which houses the routinely collected health care data for over 14 million residents. The utilization of these data was approved in accordance with section 45 of Ontario’s Personal Health Information Protection Act, which does not require review by a research ethics board. Our findings are in accordance with the Reporting of studies Conducted using Observational Routinely Collected Data reporting guidelines for observational research using routinely gathered data.¹²

Data Sources

We linked several data sets using unique encoded identifiers and analyzed data at ICES. Vital statistics and demographic details were obtained from the Ontario Registered Persons Database. The Canadian Institute for Health Information Discharge Abstract Database provided hospitalizations, diagnoses, and procedural data. Diagnostic data from emergency room and day surgery visits were derived from the National Ambulatory Care Reporting System. We extracted health claims for outpatient and inpatient physician services from the Ontario Health Insurance Plan database. We extracted medication data from the Ontario Drug Benefits database.¹³ We used validated codes whenever possible for baseline characteristics and outcomes.^14–20

Participants

We identified all Ontario residents aged ≥66 years with incident hypertension between January 1, 2010, and December 31, 2017, using a previously validated case definition with 94% specificity: (1) a hospital admission with an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code for hypertension or (2) an Ontario Health Insurance Plan claim with a hypertension diagnosis followed within 1 year by either an additional Ontario Health Insurance Plan claim or a hospital admission with a hypertension diagnosis.²¹ (Table S2 included full list of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and Ontario Health Insurance Plan diagnosis codes). The index diagnosis date was defined as the second outpatient billing claim for hypertension or hospitalization with hypertension and all patients had at least 1 year of follow-up. We followed patients until a maximum follow-up date of December 31, 2021. Patients were excluded with any of the following: age <66 years old, ineligible for Ontario Health Insurance Plan (no valid health card) 1 year before index date, non-Ontario resident at index date, death on or before index date.

Exposure

Our exposure was sex assigned at birth (female versus male) identified from the Registered Persons Database. Self-reported gender is not currently captured in any Institute for Clinical Evaluative Sciences data sets.

Outcomes

We defined outcomes in the period of 2011 to 2021, with at least 1 year of follow-up after the index date. The primary cardiovascular composite outcome was a major cardiovascular event defined as any nonfatal ischemic stroke, nonfatal myocardial infarction, or congestive heart failure.^17–20 Our secondary outcomes were all-cause mortality, coronary revascularization (percutaneous coronary intervention, coronary artery bypass grafting), and cardiovascular death. Cardiovascular death was defined as the occurrence of death during a hospitalization or emergency department visit with a cardiovascular diagnosis.¹⁶

Statistical Analysis

We used descriptive characteristics by exposure status (categorical variables as frequencies and percentages, continuous variables as mean and SD for normally distributed variables, or median and interquartile range for non-normally distributed variables). Differences between exposure levels were quantified using P values from Kruskal-Wallis tests (with P<0.05 considered significant) and absolute standardized differences, with values >0.1 indicating substantive differences.²²

We examined the association between sex and time to occurrence of the primary composite cardiovascular outcome using Cox proportional hazards regression, with follow-up beginning from the index date. The proportional hazards assumption was assessed and satisfied for the exposure sex, graphically, and statistically, using a log-log survival plot.^23,24 Fine and Gray subdistributional hazard ratios (HRs) were used to account for death as a competing risk for the primary composite cardiovascular outcome and secondary outcome of revascularization and, death and cardiovascular death as competing risks for revascularization.²⁵ Models were adjusted for age, era of hypertension diagnosis (2009–2012 or 2012–2017), neighborhood income quintile (as a proxy for socioeconomic status), rural versus urban residence, number of family physician encounters in the previous year, number of hospitalizations in the previous year, number of total health care encounters in the previous year, each nonhypertension Elixhauser comorbidity (present or absent, based on a 3-year lookback).^14,15 We also adjusted for the use of medications known to lower blood pressure but prescribed for other indications based on our clinical knowledge and previous literature, ascertained in the 120 days closest to cohort entry.^26,27 Detailed covariates and outcome definitions used in the analyses are outlined in Tables S2 and S3. We tested plausible several effect modifiers of the association between sex and the primary composite cardiovascular outcome a priori and added them to the model individually: age, diabetes, era of hypertension diagnosis (200–2012 or 2012–2017), a prior cardiovascular diagnosis, and use of blood pressure–lowering medications for other conditions. We tested the P values for the interaction terms, and as they all demonstrated statistical significance, we presented all effect modifiers. We also conducted an additional analysis where we restricted to patients from the top 2 income quintiles who had visited a family physician in the past year and had no documented comorbidities at baseline, which we thought would reduce confounding due to baseline illness, socioeconomic factors, and health behaviors. Data were missing for income quintile (807, 0.3%) and rural residence (337, 0.1%), but as this represented <1% of missing data, analyses proceeded using a complete case design. We report results as HRs with 95% CIs. Two-sided P<0.05 were considered significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc).

RESULTS

Baseline Characteristics

Among a total of 1 059 026 eligible Ontario residents, 266 273 (25.1%) were ≥66 years with incident hypertension (Figure 1). Table 1 shows the baseline characteristics of the complete cohort and by sex. The mean (SD) age was 74 (7) years and 51% of the cohort were female. Females had fewer hypertension diagnoses between 2009 and 2012, and fewer diagnoses of coronary artery disease, myocardial infarction, diabetes or major cancer within 3 years before their hypertension diagnosis. Among the 154 872 (58.2%) individuals who were already prescribed medication that can lower blood pressure at the time of hypertension diagnosis, females were less likely to be prescribed alpha-blockers, ACE inhibitors, β-blockers, or nitrates. Females were more likely to be prescribed thiazide diuretics. Females were less likely to be prescribed statins. There was no statistically significant difference between sexes in hypertension diagnosed from 2013 to 2017, or by neighborhood income quintiles, rural residence, other comorbid conditions, or number of blood pressure–lowering medications at baseline.

Figure 1.

Flow diagram for cohort assembly. OHIP indicates Ontario Health Insurance Plan.

Table 1.

Baseline Characteristics Among Individuals With a New Diagnosis of Hypertension by Sex

Outcomes

The median (interquartile range) follow-up was 6.6 (4.7–9.0) years with no statistically significant difference between the sexes (P=0.4). For the primary composite cardiovascular outcome of nonfatal stroke, myocardial infarction, or congestive heart failure, there were 38 586 events in the cohort, of which 17 642 (45.7%) were among females. Compared with males, females had a lower crude incidence rate (per 1000 person-years) of the primary composite cardiovascular outcome (287.3 in females versus 311.7 in males; P<0.001). Females had a significantly lower risk of the primary composite cardiovascular outcome than males (unadjusted HR, 0.76 [95% CI, 0.75–0.78]; adjusted HR [aHR], 0.75 [95% CI, 0.73–0.76]; Figure 2) The subdistributional HR for the primary outcome accounting for the competing risk of all-cause death was 0.88 for females compared with males (95% CI, 0.86–0.91; Table 2; Table S4).

Figure 2.

Kaplan-Meier plots for the primary cardiovascular outcome (survival probability) with newly diagnosed hypertension by sex over time. BP indicates blood pressure; and CV, cardiovascular.

Table 2.

Events, Crude Incidence Rates, Unadjusted HRs, Adjusted HRs, and Fine and Gray sHRs by Sex

There were a total of 77 005 deaths, with 35 189 (45.7%) occurring in females. Compared with males, females had a lower crude incidence rate of all-cause death compared with males (238.4 per 1000 person-years in females versus 251.4 in males; P<0.001) and lower unadjusted and adjusted hazard of all-cause death compared with males (HR, 0.77 [95% CI, [0.76–0.78]; aHR, 0.72 [95% CI, 0.71–0.73], respectively). Among the 9234 participants with cardiovascular deaths, 4020 (43.5%) deaths occurred in females. Compared with males, females had a lower crude incidence rate of cardiovascular-related death compared with males (395.7 per 1000 person-years in females versus 439.6 in males, P<0.001), and a lower hazard for cardiovascular death than males (HR, 0.88 [95% CI, 0.84–0.92]; aHR, 0.85 [95% CI, 0.82–0.99]). There were a total of 24 031 revascularization events, with 6976 (29.0%) in females. Compared with males, females had a lower crude incidence rate of revascularization compared with males (398.8 per 1000 person-years in females versus 482.3 in males; P<0.001). Females had a lower hazard for undergoing a revascularization procedure (HR, 0.86 [95% CI, 0.84–0.89]; aHR, 0.91 [95% CI, 0.89–0.94]), even after accounting for all-cause death (subdistributional HR, 0.47 [95% CI, 0.46–0.49]) and cardiovascular death (subdistributional HRs, 0.45 [95% CI, 0.43–0.46]; Table 2).

Stratified Analyses

Older age, diabetes, a previous cardiovascular diagnosis, earlier hypertension diagnosis, and preexisting use of blood pressure–lowering medication were statistically significant effect modifiers of the primary composite cardiovascular outcome (P≤0.01; Figure S1). In stratified analyses comparing females to males, females had a lower hazard of the primary composite cardiovascular outcome regardless of whether they had a previous cardiovascular diagnosis (aHR, 0.91 [95% CI, 0.83–0.99] versus aHR, 0.75 [95% CI, 0.73–0.77]), or diabetes (aHR, 0.82 [95% CI, 0.79–0.86] versus aHR, 0.73 [95% CI, 0.72–0.75]), or a more recent versus remote diagnosis of hypertension (aHR, 0.74 [95% CI, 0.71–0.76] versus aHR, 0.77 [95% CI, 0.74–0.79]), or when prescribed ≤1 blood pressure–lowering medications or not (aHR, 0.77 [95% CI, 0.75–0.78] versus aHR, 0.68 [95% CI, 0.64–0.73]).

Additional Analysis

An additional analysis conducted on a subgroup of 3635 individuals from the top 2 income quintiles who had visited a family physician was consistent in demonstrating an association between female sex and lower risk of the primary composite cardiovascular outcome (HR, 0.72 [95% CI, 0.59–0.88]).

DISCUSSION

In this population-based study of newly diagnosed hypertension in older adults, females had a lower risk of cardiovascular events than males. This was consistent for our primary composite cardiovascular outcome (stroke, myocardial infarction, and heart failure), cardiovascular death, revascularization, and all-cause death in crude and adjusted analyses accounting for the competing risk of death, as well as across all postulated effect modifiers (previous cardiovascular disease, diabetes, era of hypertension diagnosis, use of blood pressure–lowering medication).

Our findings suggest that older females with newly diagnosed hypertension are not at higher risk of cardiovascular outcomes and death compared with older males, despite existing estimates from nonrisk-adjusted cohorts and studies of younger adults suggesting otherwise.^9,10,28,29 This illustrates the importance of consideration of incident hypertension in older adults. Current evidence on sex-specific outcomes for incident hypertension in older populations is limited and, as a result, evidence from younger cohorts is extrapolated.^9,10 In contrast to our findings, previous studies have documented higher complication rates in hypertensive females compared with males; however, these findings are typically derived from younger cohorts. In a large observational study, females (age, 40–69 years) with hypertension had a 36% higher risk of stroke compared with males.³⁰ The Framingham study reported a higher risk of incident heart failure in females compared with males.⁸ The IDACO study (International Database of Ambulatory Blood Pressure in Relation to Cardiovascular Outcome) found that a 15 mm Hg increase in systolic blood pressure was more strongly associated with adverse cardiovascular events in females compared with males but with much lower crude incidence rates of 11 to 12 per 1000 person-years for death and cardiovascular outcomes than found in our study.⁹ Statistical inference from these studies is limited, as the prevalence of hypertension complications is higher in females due to their longer life expectancy and these studies do not adjust for the competing risk of death.³¹ Indeed, a registry cohort of younger patients with incident hypertension (median age, 56 years for females and 53 years for males), demonstrated that males were on more blood pressure–lowering medications, which could indicate that they have more difficult-to-control hypertension. Additionally, males in our study were more likely than females to have diabetes at the time of hypertension diagnosis, which is an indication for prescribing ACE inhibitors. However, our model accounted for the number of blood pressure–lowering medications and findings persisted in stratified analyses by both preexisting diabetes and the preexisting presence of blood pressure–lowering medication. Ultimately, prospective studies of sex-based outcome differences after incident hypertension diagnosis and population-based studies of sex-specific treatment processes and outcomes are required to untangle these complex causal pathways.

Although our findings are strengthened by our large cohort size and consistency across stratified analyses, they also have limitations. First, we lacked specific information on blood pressure measurement data. Although our findings consistently demonstrated a lower risk of cardiovascular outcomes and death for females in all analyses, we are unable to comment on differences in outcomes based on the degree of hypertension treatment between the sexes. Second, our findings are limited to sex-based findings and cannot be extrapolated to gender, although there is a strong literature base on the influence of gender as a social construct for hypertension outcomes.^10,32–37 We also lacked the racial and ethnic composition of our cohort. Third, we were unable to include some key variables related to menopausal and reproductive history, such as gestational hypertension and preeclampsia, which predisposes females to hypertension. Fourth, body mass index measurements, cholesterol data, and smoking status were unavailable in our data sets. As smoking is a risk factor for cardiovascular outcomes and death, and is more common among males, this would serve as a potential confounder.³⁸ Finally, our study is limited to a single health care system.

In our population-level, observational study of 266 273 people with late-onset hypertension, we found that there are sex-specific differences in cardiovascular outcomes and death. Importantly, and contrary to what has been observed among younger cohorts where females with hypertension are higher risk for cardiovascular events, female sex was protective against adverse cardiac outcome among older patients with hypertension in our current study. Given the high incidence of hypertension in this patient cohort, future studies should identify potential sex-specific variations in the diagnosis and management of hypertension. This approach will promote targeted and personalized approaches to hypertension management and optimize clinical outcomes.

PERSPECTIVES

This study shows that older females with newly diagnosed hypertension have a lower risk of cardiovascular outcomes and death compared with older males. This may be related to underlying biology, awareness and hypertension management, and psychosocial factors. Given the high incidence of hypertension observed in this study, these findings are particularly important in the context of a growing older population. Future studies should identify potential sex-specific variations in the diagnosis and management of hypertension. This approach will promote targeted and personalized approaches to hypertension management and optimize clinical outcomes in both sexes.

ARTICLE INFORMATION

Acknowledgments

This study was supported by the Institute for Clinical Evaluative Sciences (ICES) Ottawa site. ICES is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The opinions, results, and conclusions are those of the authors and are independent from the funding sources. Parts of this material are based on data or information compiled and provided by the Canadian Institute for Health Information. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.

Sources of Funding

None.

Disclosures

A.J. Vinson has accepted consultancy funding from Paladin Labs, Inc, and Takeda Pharmaceuticals. The other authors report no conflicts.