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Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: a systematic review and meta-analysis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2018 (English)In: JAMA Internal Medicine, ISSN 2168-6106, E-ISSN 2168-6114, Vol. 178, no 1, p. 28-36Article in journal (Refereed) Published
Abstract [en]

Importance: High blood pressure (BP) is the most important risk factor for death and cardiovascular disease (CVD) worldwide. The optimal cutoff for treatment of high BP is debated.

Objective: To assess the association between BP lowering treatment and death and CVD at different BP levels.

Data sources: Previous systematic reviews were identified from PubMed, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effect. Reference lists of these reviews were searched for randomized clinical trials. Randomized clinical trials published after November 1, 2015, were also searched for in PubMed and the Cochrane Central Register for Controlled Trials during February 2017.

Study selection: Randomized clinical trials with at least 1000 patient-years of follow-up, comparing BP-lowering drugs vs placebo or different BP goals were included.

Data extraction and synthesis: Data were extracted from original publications. Risk of bias was assessed using the Cochrane Collaborations assessment tool. Relative risks (RRs) were pooled in random-effects meta-analyses with Knapp-Hartung modification. Results are reported according to PRISMA guidelines.

Main outcomes and measures: Prespecified outcomes of interest were all-cause mortality, cardiovascular mortality, major cardiovascular events, coronary heart disease (CHD), stroke, heart failure, and end-stage renal disease.

Results: Seventy-four unique trials, representing 306 273 unique participants (39.9% women and 60.1% men; mean age, 63.6 years) and 1.2 million person-years, were included in the meta-analyses. In primary prevention, the association of BP-lowering treatment with major cardiovascular events was dependent on baseline systolic BP (SBP). In trials with baseline SBP 160 mm Hg or above, treatment was associated with reduced risk for death (RR, 0.93; 95% CI, 0.87-1.00) and a substantial reduction of major cardiovascular events (RR, 0.78; 95% CI, 0.70-0.87). If baseline SBP ranged from 140 to 159 mm Hg, the association of treatment with mortality was similar (RR, 0.87; 95% CI, 0.75-1.00), but the association with major cardiovascular events was less pronounced (RR, 0.88; 95% CI, 0.80-0.96). In trials with baseline SBP below 140 mm Hg, treatment was not associated with mortality (RR, 0.98; 95% CI, 0.90-1.06) and major cardiovascular events (RR, 0.97; 95% CI, 0.90-1.04). In trials including people with previous CHD and mean baseline SBP of 138 mm Hg, treatment was associated with reduced risk for major cardiovascular events (RR, 0.90; 95% CI, 0.84-0.97), but was not associated with survival (RR, 0.98; 95% CI, 0.89-1.07).

Conclusions and relevance: Primary preventive BP lowering is associated with reduced risk for death and CVD if baseline SBP is 140 mm Hg or higher. At lower BP levels, treatment is not associated with any benefit in primary prevention but might offer additional protection in patients with CHD.

Place, publisher, year, edition, pages
2018. Vol. 178, no 1, p. 28-36
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:umu:diva-143058DOI: 10.1001/jamainternmed.2017.6015ISI: 000419113300009PubMedID: 29131895OAI: oai:DiVA.org:umu-143058DiVA, id: diva2:1166260
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-06-09Bibliographically approved
In thesis
1. Effect of antihypertensive treatment at different blood pressure levels
Open this publication in new window or tab >>Effect of antihypertensive treatment at different blood pressure levels
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

High blood pressure is associated with an increased risk of cardiovascular disease and premature death. The shape of association between blood pressure and the risk of cardiovascular events is debated. Some researchers suggest that the association is linear or log-linear, whereas others suggest it is J-shaped. Randomized controlled trials of antihypertensive treatment have been successful in hypertension, but ambiguous in the high normal blood pressure range. Previous systematic reviews have not found any interaction between baseline systolic blood pressure and treatment effect, with beneficial effects at systolic blood pressure levels well below what is currently recommended. These reviews, however, use a method to standardize treatment effects and study weights according to within-trial blood pressure differences that may introduce bias.

Methods

We performed two systematic reviews to assess the effect of antihypertensive treatment on cardiovascular disease and mortality at different blood pressure levels. The first review was limited to people with diabetes mellitus. The second review included all patient categories except those with heart failure and acute myocardial infarction. Both reviews were designed with guidance from Cochrane Collaborations Handbook for Systematic Reviews of Interventions, and are reported according to PRISMA guidelines. We included randomized controlled trials assessing any antihypertensive agent against placebo or any blood pressure targets against each other. Results were combined in random-effects meta-analyses, stratified by baseline systolic blood pressure. Non-stratified analyses were performed for coronary heart disease trials and post-stroke trials. Interaction between blood pressure level and treatment effect was assessed with Cochran’s Q in the first review, and multivariable-adjusted metaregression in the second review.

The third paper builds on data from the second paper, and assesses the effect of standardization according to within-trial blood pressure differences on the results of meta-analyses. We performed non-standardized analyses, analyses with standardized treatment effects, and analyses with standardized treatment effects and standard errors. We compared treatment effect measures and heterogeneity across different methods of standardization. We also compared treatment effect estimates between fixed-effects and random-effects meta-analyses within each method of standardization. Lastly, we assessed the association between number of events and study weights, using linear regression.

Results

Forty-nine trials assessed the effect of antihypertensive treatment in people with diabetes mellitus. Treatment effect on cardiovascular mortality and myocardial infarction decreased with lower baseline systolic blood pressure. Treatment reduced the risk of death and cardiovascular disease if baseline systolic blood pressure was 140 mm Hg or higher. If baseline systolic blood pressure was below 140 mm Hg, however, treatment increased the risk of cardiovascular death by 15 % (0-32 %).

Fifty-one trials assessed the effect of antihypertensive treatment in primary prevention. Treatment effect on cardiovascular mortality, major cardiovascular events, and heart failure decreased with lower baseline systolic blood pressure. If baseline systolic blood pressure was 160 mm Hg or higher treatment reduced the risk of major cardiovascular events by 22 % (95 % confidence interval 13-30 %). If systolic blood pressure was 140-159 mm Hg treatment reduced the risk by 12 % (4-20 %), whereas if systolic blood pressure was below 140 mm Hg, treatment effect was neutral (4 % increase to 10 % reduction). All-cause mortality was reduced if systolic blood pressure was 140 mm Hg or higher, with neutral effect at lower levels.

Twelve trials compared antihypertensive treatment against placebo in people with coronary heart disease. Mean baseline systolic blood pressure was 138 mm Hg. Treatment reduced the risk of major cardiovascular events by 10 % (3-16 %), whereas the effect on mortality was neutral (7 % increase to 11 % reduction).

Standardization of treatment effects resulted in more extreme effect estimates for individual trials. This caused increased between-study heterogeneity, and different results with fixed- and random-effects model. Standardization of standard errors shifted weights from trials with many events to trials with large blood pressure differences. This caused biased overall effect estimates. Standardization of standard errors also resulted in wider confidence intervals, masking the previously increased heterogeneity. This reduced the possibility to find different treatment effects at different blood pressure levels.

Conclusion The effect of antihypertensive treatment depends on blood pressure level before treatment. Treatment reduces the risk of death and cardiovascular disease if baseline systolic blood pressure is 140 mm Hg or higher. Below this level, treatment is potentially harmful in people with diabetes, has neutral effect in primary prevention, but might offer additional protection in people with coronary heart disease. Standardization should generally be avoided in meta-analyses of antihypertensive treatment. Previous meta-analyses using standardized methods should be interpreted with caution.

Abstract [sv]

Hjärt-kärlsjukdomar leder till fler dödsfall och fler förlorade levnadsår än någon annan sjukdomsgrupp. Den enskilt viktigaste riskfaktorn som bidrar till hjärtkärlsjukdomar ur ett befolkningsperspektiv är högt blodtryck. Risken att drabbas av hjärt-kärlsjukdomar minskar om man behandlar högt blodtryck men till vilken nivå blodtrycket skall behandlas är kontroversiellt.

Denna avhandling innefattar två systematiska översikter och meta-analyser samt ett arbete som jämför olika sätt att hantera skillnader mellan studier i meta-analyser. De systematiska översikterna sammanställer data från randomiserade kontrollerade studier av blodtryckssänkande behandling. Vår övergripande frågeställning var om effekten av behandling påverkas av blodtrycksnivån innan behandling. Mer specifikt studerades hur behandling påverkade risken att dö eller drabbas av hjärt-kärlsjukdom vid olika blodtrycksnivåer.

Det första arbetet fokuserade på personer med diabetes. För dessa fann vi att blodtryckssänkande behandling minskar risken att dö eller drabbas av hjärtkärlsjukdom vid nivåer ≥ 140 mmHg. Vi fann ingen nytta, men möjligen en skadlig effekt av behandling, vid lägre blodtrycksnivåer. Det andra arbetet inkluderade studier oberoende av vilka sjukdomar deltagarna hade. Vi fann att den förebyggande effekten av blodtryckssänkande behandling berodde på blodtrycksnivån. Vid blodtryck > 160 mmHg minskade risken att drabbas av hjärt-kärlsjukdomar med 22 % hos de som erhöll behandling. Om blodtrycket var 140-160 mmHg minskade risken med 12 %, men om blodtrycket var < 140 mmHg sågs ingen behandlingseffekt. Hos personer med känd kranskärlssjukdom, och ett medelblodtryck på 138 mmHg, fann vi en något minskad risk för hjärt-kärlhändelser med ytterligare behandling. I det tredje arbetet fann vi att skillnader i resultat mellan olika studier inte kan antas bero endast på olika grad av blodtryckssänkning i studierna. När resultaten standardiserades, som om alla studier hade sänkt blodtrycket lika mycket, ökade nämligen skillnaderna mellan studierna. Detta resulterade i sin tur i snedvridning av resultaten från meta-analyser av standardiserade värden.

Sammanfattningsvis minskar blodtryckssänkande behandling risken att dö eller drabbas av hjärt-kärlsjukdomar om blodtrycket är 140 mmHg eller högre. Vid lägre nivåer är nyttan med behandling osäker samtidigt som det finns potentiella risker. Standardisering bör inte användas rutinmässigt vid metaanalyser av blodtrycksstudier. Tidigare meta-analyser som använt denna metod bör tolkas med försiktighet.

Place, publisher, year, edition, pages
Umeå: Department of Public Health and Clinical Medicine, Umeå University, 2017. p. 78
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1936
Keyword
blood pressure, hypertension, antihypertensive treatment, cardiovascular disease, randomized controlled trial, systematic review, meta-analysis, standardization
National Category
Clinical Medicine Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-143061 (URN)978-91-7601-816-3 (ISBN)
Public defence
2018-01-26, Hörsal D, Unod T9, 9 tr., Norrlands Universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2017-12-20 Created: 2017-12-15 Last updated: 2018-06-09Bibliographically approved

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