Blood pressure targets for hypertension in patients with type 2 diabetes

Introduction

One of the main goals in managing type 2 diabetes in adults is prevention of cardiovascular morbidity or mortality by controlling blood glucose, normalizing blood pressure, and reducing other cardiovascular risk factors (1,2). Despite extensive review of literature, clinical practice guidelines vary in determining the optimal blood pressure targets in patients with diabetes (3-5).

To support clinical decisions at point of care with all available evidence, we conducted a rapid review of the published and unpublished data from recently completed randomized controlled trials (RCT), meta-analyses of RCTs, and primary observational studies that compared different blood pressure targets in adults with diabetes.

Methods

We used a standard recommended methodology in conducting systematic literature reviews and meta-analyses from the Cochrane Collaboration and the Agency for Healthcare Research and Quality (6,7). We developed a priori protocol (available by request) for a systematic literature review to answer the clinical question about the comparative effectiveness of blood pressure targets on mortality and cardiovascular morbidity in adults with diabetes mellitus.

Eligible studies directly compared lower versus higher blood pressure targets or examined the association between baseline or attained blood pressure with patient outcomes in people treated with hypotensive medications. Eligible outcomes included all-cause and underlying cause-specific mortality, cardiovascular morbidity, stroke, heart failure, renal failure, and all drug harms.

We conducted a comprehensive search in PubMed, EMBASE, the Cochrane Library, and www.clinicaltrials.gov up to March 2018 to find systematic reviews, published and unpublished RCTs, and nationally represented controlled observational studies that reported adjusted effect estimates (6,7). The data were extracted from the Clinical Trials Transformation Initiative (https://www.ctti-clinicaltrials.org/aact-database), checked for quality, and stored in the High-Performance Computing Cluster platform (https://hpccsystems.com).

We tested the null hypotheses of no differences in patient outcomes after more versus less extensive blood pressure lowering (6). We abstracted the information about study population, interventions, comparators, and outcomes (6). We abstracted minimum datasets (e.g., number of the subjects in treatment groups and events) to estimate absolute risk difference, relative risk, and number needed to treat for categorical variables (6). Statistical significance was evaluated at a 95% confidence level (including the use of P values).

We conducted a rapid review following the framework of the AHRQ (8). We used the AHRQ recommended methodological approach in the integration of existing systematic reviews into our comprehensive synthesis of evidence (9). Our goal was the integration of previously published high quality reviews and consistent ranking of the quality of evidence using GRADE methodology.

We performed meta-analyses when definitions of active and control interventions and patient outcomes deem similar (10). We examined consistency in results across studies with chi-square tests and I² statistics and concluded statistically significant heterogeneity if I² was >50% (6). Statistically significant heterogeneity did not preclude statistical pooling (10). However, we planned exploring heterogeneity with a priori defined patient baseline hypertensive status (10).

We defined harms as the totality of all possible adverse consequences of an intervention.

We calculated absolute risk difference, number needed to treat, and the number of attributable events based on data from the published randomized trials, using STATA software (StataCorp LP, College Station, TX, USA) (11). Correction coefficients for zero events were used as a default option, and intention to treat was used for evidence synthesis (10). Superiority of interventions under comparison was hypothesized (12). We used consensus method guidelines for systematic review and meta-analyses that do not recommend conducting post hoc analyses of statistical power (13-15). Instead, we downgraded our confidence in true treatment effects based on calculated optimal information size as the number of patients required for an adequately powered individual trial (16). Since power is more closely related to number of events than to sample size, we concluded imprecision in treatment effects if less than 250 patients experienced the event (16).

We assessed reporting bias as a proportion of published among all registered studies, unreported outcomes compared with published protocols, or unreported minimum data sets for reproducibility of the results (17). We did not conduct formal statistical tests for publication bias due to the questionable validity of such tests (18).

We evaluated the quality of the primary studies using the Cochrane risk of bias tool on a 3-point scale: high bias, low bias, and unclear (6). We upgraded the risk of bias in the body of evidence from low to high if at least 1 RCT had high risk of bias (19,20). We defined indirectness in outcomes from intermediate outcomes (21).

Treatment effect estimates were defined as precise when pooled estimates had reasonably narrow 95% confidence intervals (CI) and the number of events were greater than 250 (22). Justification of the sample size was not included in grading of the evidence.

In assessing the quality of evidence in all studies, the authors looked for the strength of association and evidence of any reporting bias (23). The strength of the association was evaluated, defining a priori a large effect when the relative risk was greater than 2 and a very large effect when the relative risk was greater than 5 (23). A small treatment effect was construed when the relative risk was significant but less than 2 (23).

The authors assigned the quality of evidence ratings as high, moderate, low, or very low, according to risk of bias in the body of evidence, directness of comparisons, precision and consistency in treatment effects, and the evidence of reporting bias, using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (Supplementary file) (23). A high quality of evidence was assigned to well-designed RCTs with consistent findings. The quality of evidence was downgraded to moderate if at least 1 of 4 quality of evidence criteria were not met; for example, moderate quality of evidence was assigned if there was a high risk of bias in the body of evidence or if the results were not consistent or precise (23). The quality of evidence was downgraded to low if 2 or more criteria were not met.

A low quality of evidence was assigned to nonrandomized studies and upgraded for the rating if there was a strong association. Evidence was defined as insufficient when no studies provided valid information about treatment effects. This approach was applied regardless of whether the results were statistically significant.

Results

Our comprehensive search in PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov up to March 2018 retrieved 306 references and identified 16 publications of systematic reviews and meta-analyses and 96 publications of RCTs that enrolled adults primarily with type 2 diabetes mellitus (Supplementary file, Figure S1). We excluded 124 irrelevant references at the screening of the titles and abstracts and 33 publications after full text review because the studies did not address blood pressure targets in patients with diabetes (Supplementary file, Figure S1). Only 6 primary RCTs randomly assigned patients to lower versus higher blood pressure targets and compared systolic blood pressure (SBP) targets in patients with baseline arterial hypertension (24,25) or diastolic blood pressure (DBP) targets in patients with normal (26,27) or elevated baseline blood pressure (28,29). All other RCTs compared hypotensive drugs with placebo or with each other. Meta-analyses of such trials explored the association of baseline or achieved blood pressure with patient outcomes (3-5,30-39).

Figure S1 Study flow diagram. Publications of primary RCTs of blood pressure targets (24-29,42-44,104-107); publications of RCTs that examined efficacy or comparative effectiveness of antihypertensive drugs in 1970–1989 (108-114), 1990–1999 (41,115-135), 2000–2002 (136-152), 2003–2005 (153-174), 2006–2009 (175-190), 2010–2014 (191-207); publications of reviews (3-5,30,31,33-38,40,50,90,93,208,209); publications of guidelines published in 2010–2014 (59,60,62-66,94,95,97,210-213) and in 2015–2018 (51-56,61,87,96,98,214-217).

In adults with diabetes and normal arterial blood pressure, low-quality evidence suggests that there are no differences in all-cause and cardiovascular mortality or morbidity between intensive (10 mmHg below baseline DBP) and moderate blood pressure control (DBP goal 80–89 mmHg; Table 1). Intensive blood pressure control prevents cerebrovascular events and progression or retinopathy in some patients (Table 1).

Table 1 The benefits and harms of intensive versus moderate diastolic blood pressure control in normotensive adults with diabetes mellitus
Full table

In adults with diabetes and elevated arterial blood pressure (DBP ≥90 mmHg), low-quality evidence suggests that there are no differences in all-cause and cardiovascular mortality or stroke between intensive (DBP ≤85–75 mmHg) and moderate blood pressure control (DBP goal 80–90 mmHg; Table 2). A single RCT suggests that a reduction of DBP ≤80 mmHg results in a lower risk of major cardiovascular events but higher risk of progressing neuropathy (Table 2).

Table 2 The benefits and harms of intensive versus moderate diastolic blood pressure control in adults with diabetes mellitus and arterial hypertension
Full table

In adults with diabetes and elevated arterial blood pressure (SBP 130–190 mmHg), moderate-quality evidence suggests that there are no differences in all-cause or cardiovascular mortality between intensive and standard blood pressure control (Table 3 and Figure 1). However, intensive blood pressure control decreases the risk of diabetes-related mortality, fatal or nonfatal stroke (Figure 2), prevalence of left ventricular hypertrophy and electrocardiogram (ECG) abnormalities, macroalbuminuria, and non-spine bone fractures (Table 3). A single RCT (ACCORD) suggests that the risk of a composite outcome (nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular causes) is lower after intensive blood pressure and good glycemic control but higher in adults with poorly controlled diabetes (hemoglobin A_1c >8.0; Table 3). The benefits from intensive blood pressure control sustain at 9 years of follow-up in older adults with 15% or greater 10-year coronary heart risk in the standard glucose control arm of ACCORD trial (Table 3). The same study reported an increased risk of adverse effects from hypotensive medications, including hypotension or hyperkalemia, after intensive blood pressure control (Table 3).

Table 3 The benefits and harms of intensive versus standard systolic blood pressure control in adults with diabetes mellitus and arterial hypertension
Full table

Figure 1 Cardiovascular outcomes after intensive versus standard systolic blood pressure control in adults with diabetes mellitus and arterial hypertension. Target systolic blood pressure <120 versus <140 mmHg in ACCORD study and 144/82 versus 154/87 mmHg in UKPDS 38 study. RR, relative risk.

Figure 2 Stroke after intensive versus standard systolic blood pressure control in adults with diabetes mellitus and arterial hypertension. Target systolic blood pressure <120 versus <140 mmHg in ACCORD study and 144/82 versus 154/87 mmHg in UKPDS 38 study.

Primary studies did not address circadian fluctuations in blood pressure or the risk of orthostatic hypotension after intensive versus standard blood pressure targets. For the record, the ACCORD study found no differences in patient falls or trauma after intensive blood pressure control (Table 3).

Published meta-analyses of aggregate data from RCTs aimed at efficacy or comparative effectiveness of specific hypotensive drugs in adults with comorbid diabetes and arterial hypertension (baseline blood pressure >150 mmHg) agree that attained SBP 130–139 and DBP 75–80 mmHg is associated with lower risk of all-cause mortality and stroke (Table S1) (5,31,33,37). Systematic reviews and guidelines vary in determining the balance between benefits and harms of lowering blood pressure below 130 mmHg (4,5). We looked at the pooled relative risk of all reported outcomes in published reviews (Table S1) and found 2 meta-analyses that reported a statistically significant increase in the risk of cardiovascular mortality in association with lower baseline blood pressure (Table S2) (31,37). Anti-hypertensive treatments are associated with a higher risk of cardiovascular mortality per each 10 mmHg lower baseline SBP and DBP (Table S2).

Table S1 Relative risk of patient outcomes depending on baseline or attained blood pressure in adults with diabetes, the results from meta-analyses of aggregate data from randomized controlled clinical trials
Full table

Table S2 GRADE summary of findings. Harms of blood pressure control in adults with diabetes mellitus (low-quality evidence from published aggregate data meta-analyses of any antihypertensive treatments)
Full table

Discussion

Our review found moderate direct quality evidence that in adults with diabetes and elevated SBP, intensive blood pressure control (target SBP <120–140 mmHg) decreases the risk of diabetes-related mortality, fatal or nonfatal stroke, prevalence of left ventricular hypertrophy and ECG abnormalities, macroalbuminuria, and non-spine bone fractures, with no differences in all-cause or cardiovascular mortality or falls.

We downgraded the quality of evidence due to risk of bias, small number of events in the studies, and heterogeneity in treatment effects across the studies. We did not conduct meta-regression of few RCTs that directly compared patient outcomes after intensive versus standard blood pressure targets (6). Instead, we reviewed published meta-analyses of RCTs aimed at comparative effectiveness of blood lowering drugs in adults with diabetes that concluded no benefits from lowering blood pressure below 130 mmHg. Such publications employed meta-regression of aggregated data that can generate hypotheses of potential harms from extensive lowering blood pressure control specifically in adults with normal baseline blood pressure (45). Published meta-analyses that included the data from the Systolic Blood Pressure Intervention Trial (SPRINT) suggest similar reduction in the risk of major cardiovascular events from intensive blood pressure lowering in adults with and without diabetes (20,38,46). Individual rather than aggregate patient data meta-analyses would provide better evidence about the association between specific drugs, baseline and achieved blood pressure, and patient outcomes independent of drug effects (47).

We found no studies that addressed the risk of hospitalization or long-term quality of life in relation to blood pressure targets in adults with diabetes. Although orthostatic hypotension is associated with poor patient outcomes, the evidence regarding the risk of this complication after intensive or standard blood pressure control is insufficient (3,48,49). Primary studies and meta-analyses did not discuss the importance of pulse pressure in reducing morbidity and mortality in adults with diabetes (50).

Guidelines recommend healthy diet, weight normalization, and physical activity for all adults with diabetes (Table S3) (51-58).

Table S3 Guideline recommendations regarding blood pressure targets in adults with diabetes
Full table

In addition to healthy lifestyle, recent guidelines recommend antihypertensive drug treatments in patients with diabetes and baseline blood pressure ≥130/80 mmHg (54-56,59-61). The American Heart Association recommends a treatment goal of <130/80 mmHg, while the American Diabetes Association recommends a treatment goal of <140/90 mmHg with lower targets in individuals at high risk of cardiovascular disease (54-56,59-61). Other guidelines also recommend baseline cardiovascular disease risk assessment and evaluation of kidney, eye, or cerebrovascular damage in determining individual treatment goals (51,62-65). The American Geriatrics Society guidelines acknowledge the potential harm from arterial hypotension in older adults with diabetes mellitus (66). Guidelines generally agree that high quality care for patients with diabetes include normalization of HbA1C without hypoglycemia (67-69). This definition of high quality care for patients with diabetes should include normalization of blood pressure including pulse pressure without hypotension.

Regardless of the intended blood pressure goal, the ability to maintain a lower blood pressure threshold in a real-world setting outside of a controlled trial is an important disease management consideration (70). It is often reported that more than half of treated patients are not able to maintain blood pressure control, even at a threshold of <140/85 mmHg (71). Findings from the DIALOGUE study (72), a multicenter prospective registry among patients with hypertension and type II diabetes, demonstrated that patients with a “strict” SBP target (≤130 mmHg) had more contacts with general practitioners than any other patient group. In addition, among patients with a lower blood pressure target, only half actually maintained this threshold over 6 months. More specifically, 53% of patients in the “strict” target group (≤130 mmHg) were able to maintain this blood pressure goal over time, and 55% of patients in the “medium” target group (130 to ≤135 mmHg) were able to do so.

The majority of the studies relied on office measurements of blood pressure rather than ambulatory blood pressure monitoring. However, ambulatory blood pressure monitoring improves baseline and post-treatment risk assessment (73-86). Evidence-based guidelines recommend ambulatory blood pressure monitoring for diagnosis and individualization of treatment goals in adults with arterial hypertension (51,56,87-89).

Our review has several limitations. We analyzed direct evidence from RCTs that randomly assigned patients to more versus less intensive blood pressure goals and did not abstract the data from RCTs aimed at efficacy or comparative effectiveness of hypotensive drugs. We could not reproduce the results from meta-regression, because the authors did not provide sufficient data (30,33,35-38,90). We did not contact authors of meta-analyses requesting reproducible data. We do not know how many unregistered and unpublished studies analyzed the association between baseline and attained blood pressure and patient outcomes.

Despite this limitation, we present conflicting evidence from all published and unpublished studies appraised with consistent GRADE methodology. In contrast with previous meta-analyses of direct evidence, we grouped studies by baseline hypertension status and by targeted diastolic and SBP targets (38,40).

Our review has implications for clinical practice. Clinicians should assess baseline cardiovascular risk, recommend behavioural and pharmacological treatments aiming at blood pressure normalization without hypotension or orthostatic hypotension (91). They should engage patients in life style optimization, blood pressure self-monitoring, and monitoring of drug adverse effects (92).

Our review has policy implications. High quality care in patients with diabetes and arterial hypertension should be defined as achievement of normal blood pressure without episodes of hypotension and with minimal risk of orthostatic hypotension or other serious harms from recommended drugs.

Our review has research implications. Future research should determine the optimal blood pressure targets in subpopulations with diabetes and various demographic, socioeconomic, and behavioral factors, as well as comorbidities. Composite outcomes should be avoided. Trials should use blood pressure monitoring and examine pulse pressure, the risk of orthostatic hypotension and other drug-related harms in determining optimal choice of drugs and blood pressure targets in individual patients.

Conclusions

Based on our review, we conclude that in adults with diabetes and arterial hypertension, in order to reduce the risk of stroke, left ventricular hypertrophy and ECG abnormalities, macroalbuminuria, and non-spine bone fractures, clinicians should encourage healthy lifestyle choices and antihypertensive medications targeting blood pressure of 120–130/80 mmHg, with close monitoring of daily blood pressure fluctuations, episodes of orthostatic hypotension, and other drug-related harms.

PICO question this report is addressing:

What are the benefits and harms of “lower” blood pressure targets compared to “standard” blood pressure targets in high-risk diabetic patients?

Study eligibility

Inclusion criteria

Exclusion criteria

Search strategy

The medical librarian develops specific search strategies based on the PICOs formulated by our clinical and epidemiology staff. We search for all relevant articles published in English from 2010 up to March 2018 in PubMed, EMBASE, and the Cochrane Library. To identify grey unpublished data, we conduct a search of the trial registry clinicaltrials.gov.

We conduct the following searches:

PubMed searches for:

• RCTs;
• Observational studies of harms (multivariate adjusted estimates from nationally representative cohorts or administrative databases) (6,7);
• Clinical practice guidelines.

EMBASE searches for full publications of:

• RCTs;
• Observational studies (multivariate adjusted estimates from nationally representative cohorts or administrative databases).

The bibliographies of identified articles are scanned, and study investigators are contacted for additional publications.

Study selection

The study epidemiologist and an author-subject matter expert contribute equally to resolving differences and decide the determination of eligibility collaboratively.

The study epidemiologist and an author-subject matter expert determine eligibility for full text review, first screen title, and abstracts. All citations found during the searches are stored in a reference database.

Data extraction and strategy for data synthesis

Data extraction

The data was extracted from the Clinical Trials Transformation Initiative (https://www.ctti-clinicaltrials.org/aact-database), checked for quality, and stored in the HPCC platform (High-Performance Computing Cluster, https://hpccsystems.com/).

We manually abstracted the data from published articles into the abstraction form. We checked the data for ambiguity (i.e., data reported in percentiles conflicting with unit data and vice versa; values outside a normal range) and mismatch with the published data. Identified errors have been discussed and corrected.

We abstract the information about study population, interventions, comparators, and outcomes. We abstract minimum datasets (e.g., number of the subjects in treatment groups and events) to estimate absolute risk difference, relative risk, and number needed to treat for categorical variables.

Means and standard deviations of continuous variables, e.g., total scores from the quality of life scales are abstracted. Statistical significance is evaluated at a 95% confidence level (including the use of P values). All authors have access to the data.

We conduct an overview of the reviews following the framework of the Cochrane Collaboration. We perform meta-analyses or update published meta-analyses. Pooling criteria include the exact same definitions of the active and control intervention, patient outcomes, and similar follow-up time (10).

We define harms as the totality of all possible adverse consequences of an intervention. Investigators sometimes defined harmful effects as unrelated to examined treatments. Harms are analyzed regardless of how investigators related them to treatments.

We calculate absolute risk difference, number needed to treat, and the number of attributable events based on data from the published randomized trials, using STATA software. Correction coefficients for zero events are used as a default option in both software programs, and intention to treat is used for evidence synthesis. Superiority of interventions under comparison is hypothesized.

We assess reporting bias as a proportion of published among all registered studies, unreported outcomes compared with published protocols, or unreported minimum data sets for reproducibility of the results. We did not conduct formal statistical tests for publication bias due to the questionable validity of such tests (18).

To examine the role of patient characteristics, a search is undertaken for subgroup analyses by patient demographics, baseline and achieved blood pressure, prior treatment response, and comorbidities in systematic reviews and randomized trials, including significant interaction effects.

Methodological assessment of the included studies

For systematic reviews (QIRs), we use the Assessment of Multiple Systematic Reviews (AMSTAR) scale to determine the methodological strength of the systematic reviews (99).

For randomized studies, we apply the Cochrane risk of bias tool. Risk of bias is assessed on a 3-point scale: high bias, low bias, and unclear (100,101). A low risk of bias is assumed when RCTs met all the risk-of-bias criteria, a medium risk of bias if at least 1 of the risk-of-bias criteria is not met, and a high risk of bias if 2 or more risk-of-bias criteria are not met. An unknown risk of bias is assigned for the studies with poorly reported risk-of-bias criteria. We assign high risk of bias to all observational studies.

For clinical practice guidelines, we use the Appraisal of Guidelines for Research and Evaluation (AGREE) II (2009) tool, which covers 23 items in 6 domains and 2 overall global ratings (102,103).

Quality assessment of the included studies and the body of evidence by outcome according to the GRADE framework

The authors assign the quality of evidence ratings as high, moderate, low, or very low, according to risk of bias in the body of evidence, directness of comparisons, precision and consistency in treatment effects, and the evidence of reporting bias, using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (23). We upgrade the risk of bias from low to high if at least 1 RCT had high risk of bias. We define indirectness in outcomes from intermediate outcomes. We review published network meta-analyses but do not conduct indirect comparisons.

Treatment effect estimates are defined as precise when pooled estimates have reasonably narrow 95% confidence intervals and the number of events are greater than 250. Justification of the sample size is not included in grading of the evidence. We do not conduct post hoc statistical power analyses.

In assessing the quality of evidence in all studies, the authors look for a dose response association, the strength of association, and evidence of any reporting bias. The strength of the association is evaluated, defining a priori a large effect when the relative risk is greater than 2 and a very large effect when the relative risk is greater than 5. A small treatment effect is construed when the relative risk was significant but less than 2. For standardized continuous measures of secondary and intermediate outcomes, the magnitude of the effect is defined according to Cohen et al. as small, moderate, and large, corresponding to mean differences in standard deviation units of 0 to 0.5, 0.5 to 0.8, and greater than 0.8, respectively.

A high quality of evidence is assigned to well-designed RCTs with consistent findings. The quality of evidence is downgraded to moderate if at least 1 of 4 quality of evidence criteria is not met; for example, moderate quality of evidence is assigned if there was a high risk of bias in the body of evidence or if the results are not consistent or precise. The quality of evidence is downgraded to low if 2 or more criteria are not met.

A low quality of evidence is assigned to nonrandomized studies and upgraded for the rating if there was a strong or dose-response association. Evidence is defined as insufficient when no studies provided valid information about treatment effects. This approach is applied regardless of whether the results were statistically significant.

The authors assign strength of the recommendations based on overall quality of evidence, balances between benefits and harms, healthcare consumers’ and clinicians’ values and preferences, and cost-effectiveness studies using the GRADE methodology.

PubMed search of record:

(((((((((((((((diabet*[Title/Abstract]) OR "Diabetes Mellitus/drug therapy"[Majr])) AND (((((hypertensi*[Title/Abstract]) OR (("Blood Pressure/drug effects"[Mesh] OR "Blood Pressure/pharmacology"[Mesh] OR "Blood Pressure/therapy"[Mesh]))) OR (((("systolic blood pressure"[Title/Abstract]) OR "systolic pressure"[Title/Abstract]) OR "diastolic blood pressure"[Title/Abstract]) OR "diastolic pressure"[Title/Abstract])) OR normotensive[Title/Abstract]) OR "Hypertension/drug therapy"[Majr]))) AND ((((((strict*[Title/Abstract]) OR target*[Title/Abstract]) OR tight*[Title/Abstract]) OR intens*[Title/Abstract]) OR below[Title/Abstract]) OR moderat*[Title/Abstract])))) AND (((((("Antihypertensive Agents"[Mesh]) OR "Antihypertensive Agents" [Pharmacological Action]) OR "Angiotensin II Type 1 Receptor Blockers"[Mesh])) OR antihypertensive[Title/Abstract]) OR "angiotensin II"[Title/Abstract]))) NOT ((((((("Letter"[Publication Type]) OR "News"[Publication Type]) OR "Patient Education Handout"[Publication Type]) OR "Comment"[Publication Type]) OR "Editorial"[Publication Type])) OR "Newspaper Article"[Publication Type]))) NOT (("Animals"[Mesh]) NOT (("Animals"[Mesh]) AND "Humans"[Mesh])))) AND (((((((((random*[Title/Abstract]) OR placebo*[Title/Abstract]) OR "double blind"[Title/Abstract]) OR "triple blind"[Title/Abstract]) OR prospective[Title/Abstract]) OR multicenter[Title/Abstract])) OR "Multicenter Study" [Publication Type]) OR "Randomized Controlled Trial" [Publication Type:NoExp])))

PubMed search of record for CPGs:

(((((((((((diabet*[Title/Abstract]) OR "Diabetes Mellitus/drug therapy"[Majr])) AND (((((hypertensi*[Title/Abstract]) OR (("Blood Pressure/drug effects"[Mesh] OR "Blood Pressure/pharmacology"[Mesh] OR "Blood Pressure/therapy"[Mesh]))) OR (((("systolic blood pressure"[Title/Abstract]) OR "systolic pressure"[Title/Abstract]) OR "diastolic blood pressure"[Title/Abstract]) OR "diastolic pressure"[Title/Abstract])) OR normotensive[Title/Abstract]) OR "Hypertension/drug therapy"[Majr]))) AND ((((((strict*[Title/Abstract]) OR target*[Title/Abstract]) OR tight*[Title/Abstract]) OR intens*[Title/Abstract]) OR moderat*[Title/Abstract])))) AND (((((("Antihypertensive Agents"[Mesh]) OR "Antihypertensive Agents" [Pharmacological Action]) OR "Angiotensin II Type 1 Receptor Blockers"[Mesh])) OR antihypertensive[Title/Abstract]) OR "angiotensin II"[Title/Abstract]))) AND (((((((((((((((((((((((("Guideline"[Publication Type]) OR "Practice Guideline"[Publication Type])) OR "Consensus Development Conference"[Publication Type]) OR "Consensus Development Conference, NIH"[Publication Type]) OR "Practice Guideline"[Publication Type]) OR "Guideline"[Publication Type]) OR ((clinical[Title]) AND guideline*[Title])) OR (((clinical*[Title]) AND guide*[Title]) AND manage*[Title])) OR ((best[Title]) AND practice*[Title])) OR ((evidence[Title]) AND synthes*[Title])) OR ((consensus[Title]) AND develop*[Title])) OR ((practice[Title]) AND guideline*[Title])) OR (("evidence based"[Title]) AND guideline*[Title])) OR ((consensus[Title]) AND statement*[Title])) OR ((committee[Title]) AND opinion*[Title])) OR ((practice[Title]) AND bulletin*[Title])) OR ((clinical[Title]) AND recommendation*[Title])) OR ((("U.S. Preventive Services Task Force"[Title/Abstract]) OR USPSTF[Title/Abstract]) OR "United States Preventive Services Task Force"[Title/Abstract])) OR ACR Appropriateness Criteria[Title])) NOT ((((((("Letter"[Publication Type]) OR "News"[Publication Type]) OR "Patient Education Handout"[Publication Type]) OR "Comment"[Publication Type]) OR "Editorial"[Publication Type])) OR "Newspaper Article"[Publication Type]))) NOT (("Animals"[Mesh]) NOT (("Animals"[Mesh]) AND "Humans"[Mesh])))))

Acknowledgements

We thank David R. Goldmann, MD for his contribution to the development of the clinical question and review protocol. This work is supported by Elsevier Evidence-based Medicine Center.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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