Mattias Brunström

Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus : systematic review and meta-analyses

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.

Association of Blood Pressure Lowering With Mortality and Cardiovascular Disease Across Blood Pressure Levels: A Systematic Review and Meta-analysis

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.

Blood pressure treatment levels and choice of antihypertensive agent in people with diabetes mellitus : an overview of systematic reviews

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.

Standardization according to blood pressure lowering in meta-analyses of antihypertensive trials : comparison of three methodological approaches

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 (I2 = 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, R2 = 0.99 before standardization vs. P = 0.063, R2 = 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.

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 States

The 2017 US hypertension guidelines1 define hypertension as blood pressure (BP) ≥130/80 mm Hg. Treatment should start with nonpharmacological intervention, followed by combined drug treatment, if needed. Primary drugs are thiazide or thiazide-type diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and both dihydropyridine and nondihydropyridine types of calcium channel blockers. β-Blockers are not first-line drugs, unless the patient has ischemic heart disease or heart failure, which makes sense.2 The new target is BP <130/80 mm Hg for most people. In those aged ≥65 years, the target is based on systolic blood pressure (SBP) (<130 mm Hg) only, which, again, is reasonable.3 The guideline committee should be commended for emphasizing how to measure BP and for clearly describing how to diagnose hypertension. Indeed, moving toward home BP measurements should increase people’s knowledge of their cardiovascular risk and could also increase compliance. However, a stunning 46% of US adults have hypertension when the new practice guidelines are applied to the 2011 to 2014 National Health and Nutrition Examination Survey; 76% in the age group 65 to 74 years and 82% of those aged ≥75 years. One could almost say that, to avoid hypertension …

From efficacy in trials to effectiveness in clinical practice: The Swedish Stroke Prevention Study

Abstract 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 Västerbotten, using Södermanland 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 255 000 inhabitants. Differences in age and incidence of cardiovascular disease were small. During follow-up, more than 400 000 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.

Hypertension, the Swedish Patient Register, and Selection Bias

well as allowing an automated check for drug-disease interactions.4 Electronic health record implementation would be greatly aided if clinically relevant features are added to electronic systems. Physicians have broad discretion in drug prescribing, but this broad discretion comes with great responsibility. Physician education needs to incorporate a principle of conservative prescribing with high index of suspicion for adverse effects, especially for unscientific off-label uses, vigilance about indication creep, and use of unbiased drugknowledge bases.5 The lack of knowledge about drugs and their approved indication and the difficulty of keeping up with the ever-changing drug information are affecting how well patients are treated. Using computerized decision support systems, we could fill the knowledge gap by supplying drug approval status and the degree of scientific evidence at the point-of-care. When physicians prescribe medications for unscientific, off-label uses, their patients suffer adverse drug events. Patients expect that physicians base their prescriptions on scientific evidence, but 4 out of 5 drugs that are prescribed off-label are prescribed for unscientific use. Keeping current on ever-changing drug information is difficult, and it is difficult to understand why, in such an environment, we allow drug companies to promote unscientific, off-label uses of medications to physicians. The expensive and long approval process required by the US Food and Drug Administration (FDA) is exactly what produces the scientific evidence that physicians need to prescribe appropriately. Instead of weakening these institutions, we should also give them the mandate to monitor off-label use,6 as part of Risk Evaluation and Mitigation Strategies7 that would require physicians to document treatment indication as a means of monitoring off-label use; an approach that we have shown is feasible with the aid of electronic health records and computerized prescribing. We owe it to our patients to strengthen the FDA, Health Canada, and other drug regulatory bodies to protect our patients from the effects of (and promotion of) unscientific, off-label uses of medications.

Blood pressure targets in type 2 diabetes : a general perspective

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.

The Effect of Statins on the Risk of Venous Thromboembolism. A Systematic Review and Meta-analysis

The Effect of Statins on the Risk of Venous Thromboembolism. A Systematic Review and Meta-analysis

Blood Pressure Treatment in Patients with Diabetes Mellitus – A Systematic Review and Meta-Analysis

Background: It is currently recommended to treat patients with diabetes mellitus towards a target blood pressure of <130/80 mmHg. However, based on the findings of recent trials1, this concept has been challenged. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials assessing the effects of antihypertensive treatment in patients with diabetes mellitus. Preliminary analyses, based on published data only, are presented here. Additional, previously unpublished data, received through author contact, will be added. Results: A total of 32 trials, including 56 199 patients, fulfilled inclusion criteria and provided sufficient published data to be included in the preliminary analysis. All-cause mortality was reduced by 10 % (RR 0·90, 95 % CI 0·85 to 0·97). Similar results were found for myocardial infarction, stroke, congestive heart failure, and end-stage renal disease. Cardiovascular mortality showed an insignificant trend towards decrease (RR 0·88, CI 0·74 to 1·04), whereas non-cardiovascular mortality, amputation, and blindness were unaffected. Pre-specified subgroup analyses showed a trend towards increased risk of cardiovascular mortality (RR 1·52, CI 0·78 to 2·96) and myocardial infarction (RR 1·39, CI 0·74 to 2·63) in trials where the intervention group was treated to ⩽130 mmHg, whereas the risk of stroke continued to fall (RR 0·56, CI 0·38 to 0·81). Conclusions: Our results confirm the importance of treating high blood pressure in patients with diabetes mellitus. However, we show no benefit, but potential harm, if systolic blood pressure is lowered ⩽130 mmHg.