Polypill with or without Aspirin in Persons without Cardiovascular Disease

BACKGROUND

A polypill comprising statins, multiple blood-pressure–lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease.

METHODS

Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly. We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo. For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization. For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed.

RESULTS

A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo. The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00). The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10). The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the double-placebo group (hazard ratio, 0.69; 95% CI, 0.50 to 0.97). The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups.

CONCLUSIONS

Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk. (Funded by the Wellcome Trust and others; TIPS-3 ClinicalTrials.gov number, NCT01646437. opens in new tab.)

Reference: N Engl J Med 2021; 384:216-228

Association between high blood pressure and long term cardiovascular events in young adults: systematic review and meta-analysis

Objective To evaluate and quantify the future risk of cardiovascular events in young adults with high blood pressure.

Design Systematic review and meta-analysis.

Data sources Medline, Embase, and Web of Science were searched from inception to 6 March 2020. Relative risks were pooled using a random effects model and expressed with 95% confidence intervals. Absolute risk difference was calculated. Dose-response relations between blood pressure and individual outcomes were assessed by a restricted cubic spline model.

Eligibility criteria for selecting studies Studies were selected that investigated the adverse outcomes of adults aged 18-45 with raised blood pressure. The primary study outcome was a composite of total cardiovascular events. Coronary heart disease, stroke, and all cause mortality were examined as secondary outcomes.

Results Seventeen observational cohorts consisting of approximately 4.5 million young adults were included in the analysis. The average follow-up was 14.7 years. Young adults with normal blood pressure had increased risk of cardiovascular events compared with those with optimal blood pressure (relative risk 1.19, 95% confidence interval 1.08 to 1.31; risk difference 0.37, 95% confidence interval 0.16 to 0.61 per 1000 person years). A graded, progressive association was found between blood pressure categories and increased risk of cardiovascular events (high normal blood pressure: relative risk 1.35, 95% confidence interval 1.22 to 1.49; risk difference 0.69, 95% confidence interval 0.43 to 0.97 per 1000 person years; grade 1 hypertension: 1.92, 1.68 to 2.19; 1.81, 1.34 to 2.34; grade 2 hypertension: 3.15, 2.31 to 4.29; 4.24, 2.58 to 6.48). Similar results were observed for coronary heart disease and stroke. Generally, the population attributable fraction for cardiovascular events associated with raised blood pressure was 23.8% (95% confidence interval 17.9% to 28.8%). The number needed to treat for one year to prevent one cardiovascular event was estimated at 2672 (95% confidence interval 1639 to 6250) for participants with normal blood pressure, 1450 (1031 to 2326) for those with high normal blood pressure, 552 (427 to 746) for those with grade 1 hypertension, and 236 (154 to 388) for those with grade 2 hypertension.

Conclusions Young adults with raised blood pressure might have a slightly increased risk of cardiovascular events in later life. Because the evidence for blood pressure lowering is limited, active interventions should be cautious and warrant further investigation.

Reference:  BMJ 2020;370:m3222

Association of Blood Pressure Lowering With Incident Dementia or Cognitive Impairment

Question  Is there an association between blood pressure lowering with antihypertensive therapy and the incidence of dementia or cognitive impairment?

Findings  In this meta-analysis that included 12 trials with 92 135 participants for the primary outcome measure, blood pressure lowering with antihypertensive agents, compared with control, was associated with the development of a composite dementia or cognitive impairment outcome in 7.0% vs 7.5% of patients over a mean trial follow-up of 4.1 years, a difference that was statistically significant.

Meaning  Lowering blood pressure may be associated with a lower risk of dementia or cognitive impairment.

Reference: JAMA. 2020;323(19):1934-1944.

Effect of dose and duration of reduction in dietary sodium on blood pressure levels

Objective To examine the dose-response relation between reduction in dietary sodium and blood pressure change and to explore the impact of intervention duration.

Design Systematic review and meta-analysis following PRISMA guidelines.

Data sources Ovid MEDLINE(R), EMBASE, and Cochrane Central Register of Controlled Trials (Wiley) and reference lists of relevant articles up to 21 January 2019.

Inclusion criteria Randomised trials comparing different levels of sodium intake undertaken among adult populations with estimates of intake made using 24 hour urinary sodium excretion.

Data extraction and analysis Two of three reviewers screened the records independently for eligibility. One reviewer extracted all data and the other two reviewed the data for accuracy. Reviewers performed random effects meta-analyses, subgroup analyses, and meta-regression.

Results 133 studies with 12 197 participants were included. The mean reductions (reduced sodium v usual sodium) of 24 hour urinary sodium, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were 130 mmol (95% confidence interval 115 to 145, P<0.001), 4.26 mm Hg (3.62 to 4.89, P<0.001), and 2.07 mm Hg (1.67 to 2.48, P<0.001), respectively. Each 50 mmol reduction in 24 hour sodium excretion was associated with a 1.10 mm Hg (0.66 to 1.54; P<0.001) reduction in SBP and a 0.33 mm Hg (0.04 to 0.63; P=0.03) reduction in DBP. Reductions in blood pressure were observed in diverse population subsets examined, including hypertensive and non-hypertensive individuals. For the same reduction in 24 hour urinary sodium there was greater SBP reduction in older people, non-white populations, and those with higher baseline SBP levels. In trials of less than 15 days’ duration, each 50 mmol reduction in 24 hour urinary sodium excretion was associated with a 1.05 mm Hg (0.40 to 1.70; P=0.002) SBP fall, less than half the effect observed in studies of longer duration (2.13 mm Hg; 0.85 to 3.40; P=0.002). Otherwise, there was no association between trial duration and SBP reduction.

Conclusions The magnitude of blood pressure lowering achieved with sodium reduction showed a dose-response relation and was greater for older populations, non-white populations, and those with higher blood pressure. Short term studies underestimate the effect of sodium reduction on blood pressure.

Systematic review registration PROSPERO CRD42019140812.

Reference: BMJ 2020;368:m315

Association of Midlife to Late-Life Blood Pressure Patterns With Incident Dementia

Finding  In this prospective cohort study that included 4761 participants with 24-year follow-up and blood pressure measurements at midlife and at late life, those with midlife and late-life hypertension (hazard ratio, 1.49) and those with midlife hypertension and late-life hypotension (hazard ratio, 1.62) had higher risk for incident dementia compared with those who remained normotensive.

Question  Are specific midlife to late-life longitudinal blood pressure patterns associated with increased risk of dementia among older adults?

Meaning  Patterns of blood pressure in midlife and late life may be associated with differing risks for incident dementia.

Reference: JAMA. 2019;322(6):535-545. 

Association of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions

Question  Is intensive blood pressure treatment associated with less progression of small vessel ischemic disease, as reflected by cerebral white matter lesion volume?

Findings  In this substudy of a randomized clinical trial of 449 hypertensive patients with longitudinal brain magnetic resonance imaging, intensive blood pressure management to a target of less than 120 mm Hg, vs less than 140 mm Hg, was associated with a smaller increase in white matter lesion volume (0.92 cm³ vs 1.45 cm³).

Meaning  More intensive blood pressure management was associated with less progression of cerebral small vessel ischemic disease, although the difference was small.

Reference: JAMA. 2019;322(6):524-534.

Association of Office and Ambulatory Blood Pressure With Mortality and Cardiovascular Outcomes

Question  What is the association of office and ambulatory blood pressure with subsequent risk of mortality and cardiovascular outcomes?

Findings  In a population-based cohort of 11 135 adults, higher 24-hour and nighttime blood pressure readings were significantly associated with greater risks of death and cardiovascular events that included cardiovascular mortality combined with nonfatal coronary events, heart failure, or stroke. This association persisted after adjusting for other blood pressure measurements taken during an office visit or during ambulatory monitoring.

Meaning  Higher 24-hour and nighttime blood pressure readings were significantly associated with greater risks of death and a composite of cardiovascular outcomes, although statistically the incremental model improvement was small.

Reference: JAMA. 2019;322(5):409-420. 

Effect of Systolic and Diastolic Blood Pressure on Cardiovascular Outcomes

BACKGROUND

The relationship between outpatient systolic and diastolic blood pressure and cardiovascular outcomes remains unclear and has been complicated by recently revised guidelines with two different thresholds (≥140/90 mm Hg and ≥130/80 mm Hg) for treating hypertension.

METHODS

Using data from 1.3 million adults in a general outpatient population, we performed a multivariable Cox survival analysis to determine the effect of the burden of systolic and diastolic hypertension on a composite outcome of myocardial infarction, ischemic stroke, or hemorrhagic stroke over a period of 8 years. The analysis controlled for demographic characteristics and coexisting conditions.

RESULTS

The burdens of systolic and diastolic hypertension each independently predicted adverse outcomes. In survival models, a continuous burden of systolic hypertension (≥140 mm Hg; hazard ratio per unit increase in z score, 1.18; 95% confidence interval [CI], 1.17 to 1.18) and diastolic hypertension (≥90 mm Hg; hazard ratio per unit increase in z score, 1.06; 95% CI, 1.06 to 1.07) independently predicted the composite outcome. Similar results were observed with the lower threshold of hypertension (≥130/80 mm Hg) and with systolic and diastolic blood pressures used as predictors without hypertension thresholds. A J-curve relation between diastolic blood pressure and outcomes was seen that was explained at least in part by age and other covariates and by a higher effect of systolic hypertension among persons in the lowest quartile of diastolic blood pressure.

CONCLUSIONS

Although systolic blood-pressure elevation had a greater effect on outcomes, both systolic and diastolic hypertension independently influenced the risk of adverse cardiovascular events, regardless of the definition of hypertension (≥140/90 mm Hg or ≥130/80 mm Hg). (Funded by the Kaiser Permanente Northern California Community Benefit Program.)

Reference N Engl J Med 2019; 381:243-251

Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia

Question  Does intensive blood pressure control reduce the occurrence of dementia?

Findings  In this randomized clinical trial that included 9361 adults with hypertension, randomization to a systolic blood pressure target of less than 120 mm Hg compared with less than 140 mm Hg resulted in a rate of probable dementia of 7.2 vs 8.6 cases per 1000 person-years, a difference that was not statistically significant.

Meaning  Among adults with hypertension, intensive blood pressure control did not significantly reduce the risk of probable dementia.

Reference:
JAMA. 2019;321(6):553-561.

Association of Blood Pressure Classification in Korean Young Adults According to the 2017 American College of Cardiology/American Heart Association Guidelines With Subsequent Cardiovascular Disease Events

Question  Is hypertension in young adults, defined according to the 2017 American College of Cardiology/American Heart Association blood pressure guidelines, associated with the development of subsequent cardiovascular disease?

Findings  In this nationwide cohort study of 2 488 101 Koreans aged 20 through 39 years, stage 1 hypertension (systolic blood pressure, 130-139 mm Hg or diastolic blood pressure, 80-89 mm Hg) was associated with an increased risk of subsequent cardiovascular disease (hazard ratio, 1.25 for men; 1.27 for women).

Meaning  Young adults with stage 1 hypertension may be at increased risk for cardiovascular disease.

Reference 
JAMA. 2018;320(17):1783-1792.