Incremental effects of antihypertensive drugs: instrumental variable analysis

Objectives To assess the incremental effects of adding extra antihypertensive drugs from a new class to a patient’s regimen.

Design Instrumental variable analysis of data from SPRINT (Systolic Blood Pressure Intervention Trial). To account for confounding by indication—when treatments seem less effective if they are administered to sicker patients—randomization status was used as the instrumental variable. Patients’ randomization status was either intensive (systolic blood pressure target <120 mm Hg) or standard (systolic blood pressure target <140 mm Hg) treatment. Results from instrumental variable models were compared with those from standard multivariable models.

Setting Secondary data analysis of a randomized clinical trial conducted at 102 sites in 2010-15.

Participants 9092 SPRINT participants with hypertension and increased cardiovascular risk but no history of diabetes or stroke.

Main outcomes measures Systolic blood pressure, major cardiovascular events, and serious adverse events.

Results In standard multivariable models not adjusted for confounding by indication, addition of an antihypertensive drug from a new class was associated with modestly lower systolic blood pressure (−1.3 mm Hg, 95% confidence interval −1.6 to −1.0) and no change in major cardiovascular events (absolute risk of events per 1000 patient years, 0.5, 95% confidence interval −1.5 to 2.3). In instrumental variable models, the addition of an antihypertensive drug from a new class led to clinically important reductions in systolic blood pressure (−14.4 mm Hg, −15.6 to −13.3) and fewer major cardiovascular events (absolute risk −6.2, −10.9 to −1.3). Incremental reductions in systolic blood pressure remained large and similar in magnitude for patients already taking drugs from zero, one, two, or three or more drug classes. This finding was consistent across all subgroups of patients. The addition of another antihypertensive drug class was not associated with adverse events in either standard or instrumental variable models.

Conclusions After adjustment for confounding by indication, the addition of a new antihypertensive drug class led to large reductions in systolic blood pressure and major cardiovascular events among patients at high risk for cardiovascular events but without diabetes. Effects on systolic blood pressure persisted across all levels of baseline drug use and all subgroups of patients.

Reference: BMJ 2017;359:j5542

Advertisements

Trends for prevalence and incidence of resistant hypertension: population based cohort study in the UK 1995-2015

Objective To estimate the incidence and prevalence of resistant hypertension among a UK population treated for hypertension from 1995 to 2015.

Design Cohort study.

Setting Electronic health records from the UK Clinical Practice Research Datalink in primary care.

Participants 1 317 290 users of antihypertensive drugs with a diagnosis of hypertension.

Main outcome measures Resistant hypertension was defined as concurrent use of three antihypertensive drugs inclusive of a diuretic, uncontrolled hypertension (≥140/90 mm Hg), and adherence to the prescribed drug regimen, or concurrent use of four antihypertensive drugs inclusive of a diuretic and adherence to the prescribed drug regimen. To determine incidence, the numerator was new cases of resistant hypertension and the denominator was person years of those with treated hypertension and at risk of developing resistant hypertension. To determine prevalence, the numerator was total number of cases with resistant hypertension and the denominator was those with treated hypertension. Prevalence and incidence were age standardised to the 2015 hypertensive population.

Results The age standardised incidence of resistant hypertension increased from 0.93 cases per 100 person years (95% confidence interval 0.87 to 1.00) in 1996 to a peak level of 2.07 cases per 100 person years (2.03 to 2.12) in 2004. Incidence then decreased to 0.42 cases per 100 person years (0.40 to 0.44) in 2015. Age standardised prevalence increased from 1.75% (95% confidence interval 1.66% to 1.83%) in 1995 to a peak of 7.76% (7.70% to 7.83%) in 2007. Prevalence then plateaued and subsequently declined to 6.46% (6.38% to 6.54%) in 2015. Compared with patients aged 65-69 years, those aged 80 or more years were more likely to have prevalent resistant hypertension throughout the study period.

Conclusions Prevalent resistant hypertension has plateaued and decreased in recent years, consistent with a decrease in incidence from 2004 onwards. Despite this, resistant hypertension is common in the UK hypertensive population. Given the importance of hypertension as a modifiable risk factor for cardiovascular disease, reducing uncontrolled hypertension should remain a population health focus.

Reference: BMJ 2017;358:j3984

Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes

BACKGROUND

The previously published results of the Systolic Blood Pressure Intervention Trial showed that among participants with hypertension and an increased cardiovascular risk, but without diabetes, the rates of cardiovascular events were lower among those who were assigned to a target systolic blood pressure of less than 120 mm Hg (intensive treatment) than among those who were assigned to a target of less than 140 mm Hg (standard treatment). Whether such intensive treatment affected patient-reported outcomes was uncertain; those results from the trial are reported here.

METHODS

We randomly assigned 9361 participants with hypertension to a systolic blood-pressure target of less than 120 mm Hg or a target of less than 140 mm Hg. Patient-reported outcome measures included the scores on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Veterans RAND 12-Item Health Survey, the Patient Health Questionnaire 9-item depression scale (PHQ-9), patient-reported satisfaction with their blood-pressure care and blood-pressure medications, and adherence to blood-pressure medications. We compared the scores in the intensive-treatment group with those in the standard-treatment group among all participants and among participants stratified according to physical and cognitive function.

RESULTS

Participants who received intensive treatment received an average of one additional antihypertensive medication, and the systolic blood pressure was 14.8 mm Hg (95% confidence interval, 14.3 to 15.4) lower in the group that received intensive treatment than in the group that received standard treatment. Mean PCS, MCS, and PHQ-9 scores were relatively stable over a median of 3 years of follow-up, with no significant differences between the two treatment groups. No significant differences between the treatment groups were noted when participants were stratified according to baseline measures of physical or cognitive function. Satisfaction with blood-pressure care was high in both treatment groups, and we found no significant difference in adherence to blood-pressure medications.

CONCLUSIONS

Patient-reported outcomes among participants who received intensive treatment, which targeted a systolic blood pressure of less than 120 mm Hg, were similar to those among participants who received standard treatment, including among participants with decreased physical or cognitive function. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062.)

Risk of post-pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort study

Objectives To determine how soon after delivery the risk of post-pregnancy hypertension increases in women with hypertensive disorders of pregnancy and how the risk evolves over time.

Design Nationwide register based cohort study.

Setting Denmark.

Populations 482 972 primiparous women with a first live birth or stillbirth between 1995 and 2012 (cumulative incidence analyses), and 1 025 118 women with at least one live birth or stillbirth between 1978 and 2012 (Cox regression analyses).

Main outcome measures 10 year cumulative incidences of post-pregnancy hypertension requiring treatment with prescription drugs, and hazard ratios estimated using Cox regression.

Results Of women with a hypertensive disorder of pregnancy in a first pregnancy in their 20s, 14% developed hypertension in the first decade post partum, compared with 4% of women with normotensive first pregnancies in their 20s. The corresponding percentages for women with a first pregnancy in their 40s were 32% and 11%, respectively. In the year after delivery, women with a hypertensive disorder of pregnancy had 12-fold to 25-fold higher rates of hypertension than did women with a normotensive pregnancy. Rates in women with a hypertensive disorder of pregnancy were threefold to 10-fold higher 1-10 years post partum and remained twice as high even 20 or more years later.

Conclusions The risk of hypertension associated with hypertensive disorders of pregnancy is high immediately after an affected pregnancy and persists for more than 20 years. Up to one third of women with a hypertensive disorder of pregnancy may develop hypertension within a decade of an affected pregnancy, indicating that cardiovascular disease prevention in these women should include blood pressure monitoring initiated soon after pregnancy.

Reference: BMJ 2017;358:j3078

Lifestyle in progression from hypertensive disorders of pregnancy to chronic hypertension in Nurses’ Health Study II: observational cohort study

Objectives To study the association between lifestyle risk factors and chronic hypertension by history of hypertensive disorders of pregnancy (HDP: gestational hypertension and pre-eclampsia) and investigate the extent to which these risk factors modify the association between HDP and chronic hypertension.

Design Prospective cohort study.

Setting Nurses’ Health Study II (1991-2013).

Participants 54 588 parous women aged 32 to 59 years with data on reproductive history and without previous chronic hypertension, stroke, or myocardial infarction.

Main outcome measure Chronic hypertension diagnosed by a physician and indicated through nurse participant self report. Multivariable Cox proportional hazards models were used to investigate the development of chronic hypertension contingent on history of HDP and four lifestyle risk factors: post-pregnancy body mass index, physical activity, adherence to the Dietary Approaches to Stop Hypertension (DASH) diet, and dietary sodium/potassium intake. Potential effect modification (interaction) between each lifestyle factor and previous HDP was evaluated with the relative excess risk due to interaction.

Results 10% (n=5520) of women had a history of HDP at baseline. 13 971 cases of chronic hypertension occurred during 689 988 person years of follow-up. Being overweight or obese was the only lifestyle factor consistently associated with higher risk of chronic hypertension. Higher body mass index, in particular, also increased the risk of chronic hypertension associated with history of HDP (relative excess risk due to interaction P<0.01 for all age strata). For example, in women aged 40-49 years with previous HDP and obesity class I (body mass index 30.0-34.9), 25% (95% confidence interval 12% to 37%) of the risk of chronic hypertension was attributable to a potential effect of obesity that was specific to women with previous HDP. There was no clear evidence of effect modification by physical activity, DASH diet, or sodium/potassium intake on the association between HDP and chronic hypertension.

Conclusion This study suggests that the risk of chronic hypertension after HDP might be markedly reduced by adherence to a beneficial lifestyle. Compared with women without a history of HDP, keeping a healthy weight seems to be especially important with such a history.

Reference:  BMJ 2017;358:j3024

The Dietary Approaches to Stop Hypertension (DASH) diet, Western diet, and risk of gout in men: prospective cohort study

Objective To prospectively examine the relation between the Dietary Approaches to Stop Hypertension (DASH) and Western diets and risk of gout (ie, the clinical endpoint of hyperuricemia) in men.

Design Prospective cohort study.

Setting The Health Professionals Follow-up Study.

Participants 44 444 men with no history of gout at baseline. Using validated food frequency questionnaires, each participant was assigned a DASH dietary pattern score (based on high intake of fruits, vegetables, nuts and legumes, low fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats) and a Western dietary pattern score (based on high intake of red and processed meats, French fries, refined grains, sweets, and desserts).

Main outcome measure Risk of incident gout meeting the preliminary American College of Rheumatology survey criteria for gout, adjusting for potential confounders, including age, body mass index, hypertension, diuretic use, and alcohol intake.

Results During 26 years of follow-up, 1731 confirmed cases of incident gout were documented. A higher DASH dietary pattern score was associated with a lower risk for gout (adjusted relative risk for extreme fifths 0.68, 95% confidence interval 0.57 to 0.80, P value for trend <0.001). In contrast, a higher Western dietary pattern score was associated with an increased risk for gout (1.42, 1.16 to 1.74, P=0.005).

Conclusion The DASH diet is associated with a lower risk of gout, suggesting that its effect of lowering uric acid levels in individuals with hyperuricemia translates to a lower risk of gout. Conversely, the Western diet is associated with a higher risk of gout. The DASH diet may provide an attractive preventive dietary approach for men at risk of gout.

Reference: BMJ 2017;357:j1794

Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review

Background

Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs.

Methods

We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill—a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis.

Findings

Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14–23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen.

Interpretation

The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability.

Funding

National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

The Lancet, Volume 389, No. 10073, p1035–1042, 11 March 2017