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  • 1.
    Brunstrom, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lindholm, Lars H.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Perspective from Sweden on the global impact of the 2017 american college of cardiology/american heart association hypertension guidelines: a "sprint" beyond evidence in the United States2018In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 137, no 9, p. 886-888Article in journal (Other academic)
  • 2.
    Brunström, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cardiovascular outcomes in the Da Qing Diabetes Prevention Study2014In: The Lancet Diabetes & Endocrinology, ISSN 2213-8587, Vol. 2, no 7, p. 539-540Article in journal (Refereed)
  • 3.
    Brunström, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Effect of antihypertensive treatment at different blood pressure levels2017Doctoral 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.

  • 4.
    Brunström, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hypertension, the Swedish Patient Register, and Selection Bias2016In: JAMA Internal Medicine, ISSN 2168-6106, E-ISSN 2168-6114, Vol. 176, no 6, p. 862-863Article in journal (Refereed)
  • 5.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: a systematic review and meta-analysis2018In: JAMA Internal Medicine, ISSN 2168-6106, E-ISSN 2168-6114, Vol. 178, no 1, p. 28-36Article in journal (Refereed)
    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.

  • 6.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Blood pressure targets in type 2 diabetes: a general perspective2016In: Cardiovascular Endocrinology, ISSN 2162-688X, Vol. 5, no 4, p. 122-126Article, review/survey (Refereed)
    Abstract [en]

    Blood pressure targets in patients with type 2 diabetes are currently being debated. This review summarizes the current treatment recommendations provided in American and European guidelines, and findings from systematic reviews and meta-analyses published during the last decade. We critically assess the basis for the recommendations provided in relation to the evidence presented in reviews. When reviews differ in their results, we discuss the reasons for such differences. The results from recent studies in patients without diabetes and their potential implications for recommendations in patients with diabetes are commented upon. Finally, we conclude what targets are best in line with the totality of the available evidence.

  • 7.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses2016In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 352, article id i717Article, review/survey (Refereed)
    Abstract [en]

    Objective: To assess the effect of antihypertensive treatment on mortality and cardiovascular morbidity in people with diabetes mellitus, at different blood pressure levels.

    Design: Systematic review and meta-analyses of randomised controlled trials.

    Data sources: CENTRAL, Medline, Embase, and BIOSIS were searched using highly sensitive search strategies. When data required according to the protocol were missing but trials were potentially eligible, we contacted researchers, pharmaceutical companies, and authorities.

    Eligibility criteria: Randomised controlled trials including 100 or more people with diabetes mellitus, treated for 12 months or more, comparing any antihypertensive agent against placebo, two agents against one, or different blood pressure targets.

    Results: 49 trials, including 73 738 participants, were included in the meta-analyses. Most of the participants had type 2 diabetes. If baseline systolic blood pressure was greater than 150 mm Hg, antihypertensive treatment reduced the risk of all cause mortality (relative risk 0.89, 95% confidence interval 0.80 to 0.99), cardiovascular mortality (0.75, 0.57 to 0.99), myocardial infarction (0.74, 0.63 to 0.87), stroke (0.77, 0.65 to 0.91), and end stage renal disease (0.82, 0.71 to 0.94). If baseline systolic blood pressure was 140-150 mm Hg, additional treatment reduced the risk of all cause mortality (0.87, 0.78 to 0.98), myocardial infarction (0.84, 0.76 to 0.93), and heart failure (0.80, 0.66 to 0.97). If baseline systolic blood pressure was less than 140 mm Hg, however, further treatment increased the risk of cardiovascular mortality (1.15, 1.00 to 1.32), with a tendency towards an increased risk of all cause mortality (1.05, 0.95 to 1.16). Metaregression analyses showed a worse treatment effect with lower baseline systolic blood pressures for cardiovascular mortality (1.15, 1.03 to 1.29 for each 10 mm Hg lower systolic blood pressure) and myocardial infarction (1.12, 1.03 to 1.22 for each 10 mm Hg lower systolic blood pressure). Patterns were similar for attained systolic blood pressure.

    Conclusions: Antihypertensive treatment reduces the risk of mortality and cardiovascular morbidity in people with diabetes mellitus and a systolic blood pressure more than 140 mm Hg. If systolic blood pressure is less than 140 mm Hg, however, further treatment is associated with an increased risk of cardiovascular death, with no observed benefit.

  • 8.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lower blood pressure targets: to whom do they apply?2016In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 387, no 10017, p. 405-406Article in journal (Refereed)
  • 9.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Questionable Conclusions Regarding Blood Pressure End Points Reply2018In: JAMA Internal Medicine, ISSN 2168-6106, E-ISSN 2168-6114, Vol. 178, no 4, p. 575-576Article in journal (Refereed)
  • 10.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Response to 'SPRINTin context: meta-analysis of trials with baseline normotension and lowlevels of previous cardiovascular disease' Reply2018In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 36, no 7, p. 1603-1604Article in journal (Refereed)
  • 11.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    SPRINT in context: meta-analysis of trials with baseline normotension and low levels of previous cardiovascular disease2018In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 36, no 5, p. 979-986Article, review/survey (Refereed)
    Abstract [en]

    Objective: To estimate the effect of antihypertensive treatment in trials with baseline normotension and low levels of previous cardiovascular disease. To test if the results from SPRINT are compatible with those from other trials, and test the impact of SPRINT results on overall effect estimates. Methods: Systematic review and meta-analysis of randomized controlled trials with at least 1000 patient-years of follow-up, comparing antihypertensive treatment versus placebo, or different blood pressure goals against each other. Trials with at least 50% previous cardiovascular disease were excluded. Results: Sixteen trials, including 66816 participants, were included in the meta-analyses. Mean baseline SBP was 138mmHg, and mean difference between treatment arms was 5.5mmHg. Antihypertensive treatment was associated with a neutral effect on all-cause mortality [relative risk 0.98, 95% confidence interval (CI) 0.92-1.05] and major cardiovascular events (0.97, 0.91-1.03). Results from SPRINT differed significantly from those of other trials (P=0.012 for all-cause mortality; P=0.016 for major cardiovascular events), but overall effect estimates were similar when SPRINT was excluded (1.01, 0.95-1.06 for all-cause mortality; 0.98, 0.93-1.03 for major cardiovascular events). Treatment was associated with reduced risk of secondary outcomes stroke (0.84, 0.71-1.00) and heart failure (0.88, 0.78-0.98), although heterogeneity was high in the stroke analysis (I-2=54%). Conclusion: SPRINT results are not representative for trials with baseline normotension and low levels of previous cardiovascular disease. Antihypertensive treatment does not protect against death or major cardiovascular events in this setting.

  • 12.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Standardization according to blood pressure lowering in meta-analyses of antihypertensive trials: comparison of three methodological approaches2018In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 36, no 1, p. 4-15Article, review/survey (Refereed)
    Abstract [en]

    OBJECTIVE: Assess how standardization of relative risks (RRs) and standard errors (SEs), according to blood pressure differences within trials, affects heterogeneity, overall effect estimates and study weights in meta-analyses of antihypertensive treatment.

    METHOD: Data from a previous systematic review were used. Three sets of analyses were performed, using both random-effects and fixed-effects model for meta-analyses. First, we used raw data from the included trials. Second, we standardized RRs as if SBP was reduced by 10 mmHg in all trials. Third, we standardized both RRs and SEs.

    RESULTS: When RRs were standardized according to blood pressure lowering, heterogeneity between trials increased (I = 36 vs. 93% for mortality). This conferred large differences in treatment effect estimates using random-effects and fixed-effects model (RR 0.79, 95% confidence interval 0.70-0.89, respectively, 0.97, 0.94-0.99). When SEs were standardized, confidence intervals for individual trials widened, resulting in lower power to detect heterogeneity across trials. Study weights were dissociated from number of events in trials (P < 0.0001, R = 0.99 before standardization vs. P = 0.063, R = 0.05 after standardization). This induced a secondary shift in weight from trials with lower baseline SBP to trials with higher baseline SBP, resulting in exaggerated overall effect estimates.

    CONCLUSION: Standardization of RRs exaggerates differences between trials and makes meta-analyses highly sensitive to choice of statistical method. Standardization of SEs masks heterogeneity and results in biased effect estimates.

  • 13.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Thrombolysis in acute stroke2015In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 385, no 9976, p. 1394-1395Article in journal (Refereed)
  • 14.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Dahlström, John
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindholm, Lars Hjalmar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Lönnberg, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hallström, Sara
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Persson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    From efficacy in trials to effectiveness in clinical practice: The Swedish Stroke Prevention Study2016In: Blood Pressure, ISSN 0803-7051, E-ISSN 1651-1999, Vol. 25, no 4, p. 206-211Article in journal (Refereed)
    Abstract [en]

    Blood pressure treatment has shown great efficacy in reducing cardiovascular events in randomized controlled trials. If this is effective in reducing cardiovascular disease in the general population, is less studied. Between 2001 and 2009 we performed an intervention to improve blood pressure control in the county of Vasterbotten, using Sodermanland County as a control. The intervention was directed towards primary care physicians and included lectures on blood pressure treatment, a computerized decision support system with treatment recommendations, and yearly feed back on hypertension control. Each county had approximately 255000 inhabitants. Differences in age and incidence of cardiovascular disease were small. During follow-up, more than 400000 patients had their blood pressure recorded. The mean number of measurements was eight per patient, yielding a total of 3.4 million blood pressure recordings. The effect of the intervention will be estimated combining the blood pressure data collected from the electronic medical records, with data on stroke, myocardial infarction and mortality from Swedish health registers. Additional variables, from health registers and Statistics Sweden, will be collected to address for confounders. The blood pressure data collected within this study will be an important asset for future epidemiological studies within the field of hypertension.

  • 15.
    Brunström, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Peter M
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Blood pressure treatment levels and choice of antihypertensive agent in people with diabetes mellitus: an overview of systematic reviews2017In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 35, p. 435-462Article, review/survey (Refereed)
    Abstract [en]

    OBJECTIVE: Multiple systematic reviews address the effect of antihypertensive treatment in people with diabetes. Here, we summarize current systematic reviews concerning antihypertensive treatment effect at different blood pressure (BP) levels, and relative treatment effect of different antihypertensive agents.

    METHODS: We searched MEDLINE, BIOSIS, DARE and CDSR during years 2005-2016. Eligibility criteria, number of trials and participants, outcomes analysed, statistical methods used for data synthesis, and principal results were extracted for each review. Review quality was assessed using the assessment of multiple systematic reviews tool.

    RESULTS: We found four reviews concerning BP treatment level. These consistently showed that the effect of antihypertensive treatment on mortality, cardiovascular disease and coronary heart disease was attenuated at lower BP levels. If SBP was more than 140 mmHg, treatment reduced all-cause and cardiovascular mortality, cardiovascular disease, stroke, myocardial infarction and heart failure. If SBP was less than 140 mmHg, treatment increased the risk of cardiovascular death. We found eight reviews concerning choice of agent. We found no difference between angiotensin-converting enzyme inhibitors, angotensin receptor blockers, beta-blockers, calcium channel blockers and diuretics in preventing all-cause or cardiovascular mortality, combined cardiovascular disease, coronary heart disease and end-stage renal disease. Minor differences exist for stroke and heart failure. Data were limited on people with type 1 diabetes and very elderly patients with type 2 diabetes. None of the reviews concerning choice of agent included all relevant trials.

    CONCLUSION: The available evidence supports treatment in people with type 2 diabetes and SBP more than 140 mmHg, using any of the major antihypertensive drug classes.

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