Strategies to assess the validity of recommendations: a study protocol

Background Clinical practice guidelines (CPGs) become quickly outdated and require a periodic reassessment of evidence research to maintain their validity. However, there is little research about this topic. Our project will provide evidence for some of the most pressing questions in this field: 1) what is the average time for recommendations to become out of date?; 2) what is the comparative performance of two restricted search strategies to evaluate the need to update recommendations?; and 3) what is the feasibility of a more regular monitoring and updating strategy compared to usual practice?. In this protocol we will focus on questions one and two. Methods The CPG Development Programme of the Spanish Ministry of Health developed 14 CPGs between 2008 and 2009. We will stratify guidelines by topic and by publication year, and include one CPG by strata. We will develop a strategy to assess the validity of CPG recommendations, which includes a baseline survey of clinical experts, an update of the original exhaustive literature searches, the identification of key references (reference that trigger a potential recommendation update), and the assessment of the potential changes in each recommendation. We will run two alternative search strategies to efficiently identify important new evidence: 1) PLUS search based in McMaster Premium LiteratUre Service (PLUS) database; and 2) a Restrictive Search (ReSe) based on the least number of MeSH terms and free text words needed to locate all the references of each original recommendation. We will perform a survival analysis of recommendations using the Kaplan-Meier method and we will use the log-rank test to analyse differences between survival curves according to the topic, the purpose, the strength of recommendations and the turnover. We will retrieve key references from the exhaustive search and evaluate their presence in the PLUS and ReSe search results. Discussion Our project, using a highly structured and transparent methodology, will provide guidance of when recommendations are likely to be at risk of being out of date. We will also assess two novel restrictive search strategies which could reduce the workload without compromising rigour when CPGs developers check for the need of updating.

score. RESULTS: A total of 121 potentially relevant articles were identified and 12 RCTs were included. Seven RCTs tested qigong in combination with antihypertensive drugs compared with antihypertensive drugs alone.
The meta-analysis of two trials reporting adequate data suggested beneficial effects in favour of qigong [weighted mean difference, systolic blood pressure (SBP) -12.1 mmHg, 95% confidence interval (CI) -17.1 to -7.0; diastolic blood pressure -8.5 mmHg, 95% . Qigong was compared with waiting list control in two RCTs and was found to reduce SBP significantly (weighted mean difference -18.5 mmHg, 95% CI -23.1 to -13.9). In three further RCTs the comparisons made were: qigong combined with conventional therapy versus muscle relaxation combined with conventional therapy; qigong as a sole treatment versus exercise. All reported positive results in at least some of the relevant outcome measures. The methodological quality of the studies was low. CONCLUSION: There is some encouraging evidence of qigong for lowering SBP, but the conclusiveness of these findings is limited. Rigorously designed trials are warranted to confirm these results.

Study design
Systematic review

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Update of the recommendation needed (key reference). Please go to question 3.
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Given the reference above, do any of the following issues around this recommendation need to be modified? (possibility of more than one answer)
The population The intervention The comparison The outcome The quality of the evidence The direction of the recommendation Yes. Please go to question 2. No.
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How does this reference affects the existing recommendation?
Update of the recommendation needed (key reference). Please go to question 3.
Recommendation still valid (no update needed). Stop answering the questionnaire of this reference.
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3. Given the reference above, do any of the following issues around this recommendation need to be modified? (possibility of more than one answer) The population The intervention The comparison The outcome The quality of the evidence The direction of the recommendation

Abstract
Introduction: High blood pressure is common in acute ischaemic stroke and associated with a poor functional outcome. However, the management of high BP remains unclear and no large trials have been completed. telmisartan lowered BP by 6-7/2-4 mmHg over the first 90 days (p<0.001), pulse pressure (3-4 mmHg), and rate-pressure product (466 mmHg.bpm); no effect on heart rate was seen. Conclusion: This substudy of PRoFESS is the largest (1,360 patients) randomised assessment of BP lowering in patients with acute ischaemic stroke. Treatment with telmisartan lowered BP but did not alter functional dependency, death or recurrence by 90 days post stroke. However, the mean BP was only moderately elevated and the sample size was relatively small in comparison with ongoing trials of BP management in acute stroke (range 2,500-5,000).

Study design
Randomized control trial 1. Is this reference relevant to this recommendation (could be of use when considering updating this recommendation)?
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Abstract
Background: The aim of this study was to update the previous meta-analyses with the results of the recent trials, assessing the effect of CCBs treatment, compared to other drugs or placebo/top of therapy, on all cause mortality, cardiovascular death, major cardiovascular events, heart failure, myocardial infarction and stroke.
Methods: We performed a meta-analysis of randomized controlled trials that compared a long acting calcium channel blocker with another drug or placebo/top of therapy and that assessed all cause mortality and cardiovascular events. Overall estimates of effect were calculated with a fixed-effects, random effects model or Peto method. We performed also random effects meta-regression analysis to assess the influence of blood Yes. Please go to question 2. No.
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Recommendation still valid (no update needed).
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PMID 19843330
Abstract BACKGROUND: While hypertension is a leading risk factor for an initial stroke, the role of blood pressure lowering to prevent subsequent stroke is less clear. The results of recent large clinical trials investigating effects of antihypertensive agents in patients with a history of stroke have not shown a significant benefit; findings that are at odds with previous data. Our meta-analysis systematically evaluates the available, relevant trials to examine the role of antihypertensive drugs in preventing recurrent stroke. METHODS: MEDLINE, CENTRAL, and ClinicalTrials.gov were systematically searched and bibliographies from key reports were examined. All randomized, placebo-controlled trials that tested blood pressure lowering agents in patients with stroke or transient ischemic attack were identified. The results from these trials were combined and metaanalyses were performed. RESULTS: Ten studies were found to contain relevant endpoints and presented data allowing meta-analysis. Agents that lowered blood pressure reduced recurrent stroke (OR 0.71, 95% CI 0.59-0.86, P = 0.0004) and cardiovascular events (OR 0.69, 95% CI 0.57-0.85, P = 0.0004) in patients with a previous stroke or TIA. These agents did not affect the rate of myocardial infarction (OR 0.86, 95% CI 0.73-1.01, P = 0.07) or all-cause mortality (OR 0.95, 95% CI 0.83-1.07, P = 0.39) in this patient population.
CONCLUSION: Despite recent large trials showing no significant effect, in patients that have experienced a TIA or stroke, blood pressure lowering agents reduced the occurrence of subsequent stroke and cardiovascular events. The rate of myocardial infarction and all-cause mortality was unchanged.

Study design
Systematic review

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Update of the recommendation needed (key reference). Please go to question 3.

Recommendation still valid (no update needed).
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Given the reference above, do any of the following issues around this recommendation need to be modified? (possibility of more than one answer)
The population The intervention The comparison The outcome The quality of the evidence  . STUDY SELECTION: Randomised trials of blood pressure lowering drugs recording CHD events and strokes. 108 trials studied differences in blood pressure between study drug and placebo (or control group not receiving the study drug) ("blood pressure difference trials"), and 46 trials compared drugs ("drug comparison trials"). Seven trials with three randomised groups fell into both categories. The results were interpreted in the context of those expected from the largest published meta-analysis of cohort studies, totalling 958 000 people. PARTICIPANTS: 464 000 people defined into three mutually exclusive categories: participants with no history of vascular disease, a history of CHD, or a history of stroke. RESULTS: In the blood pressure difference trials beta blockers had a special effect over and above that due to blood pressure reduction in preventing recurrent CHD events in people with a history of CHD: risk reduction 29% (95% confidence interval 22% to 34%) compared with 15% (11% to 19%) in trials of other drugs.
The extra effect was limited to a few years after myocardial infarction, with a risk reduction of 31% compared with 13% in people with CHD with no recent infarct (P=0.04). In the other blood pressure difference trials (excluding CHD events in trials of beta blockers in people with CHD), there was a 22% reduction in CHD events (17% to 27%) and a 41% (33% to 48%) reduction in stroke for a blood pressure reduction of 10 mm Hg systolic or 5 mm Hg diastolic, similar to the reductions of 25% (CHD) and 36% (stroke) expected for the same difference in blood pressure from the cohort study meta-analysis, indicating that the benefit is explained by blood pressure reduction itself. The five main classes of blood pressure lowering drugs (thiazides, beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) were similarly effective (within a few percentage points) in preventing CHD events and strokes, with the exception that calcium channel blockers had a greater preventive effect on stroke (relative risk 0.92, 95% confidence interval 0.85 to 0.98). The percentage reductions in CHD events and stroke were similar in people with and without cardiovascular disease and regardless of blood pressure before treatment (down to 110 mm Hg systolic and 70 mm Hg diastolic). Combining our results with those from two other studies (the metaanalyses of blood pressure cohort studies and of trials determining the blood pressure lowering effects of drugs according to dose) showed that in people aged 60-69 with a diastolic blood pressure before treatment of 90 mm Hg, three drugs at half standard dose in combination reduced the risk of CHD by an estimated 46% and of stroke by 62%; one drug at standard dose had about half this effect. The present meta-analysis also showed that drugs other than calcium channel blockers (with the exception of non-cardioselective beta blockers) reduced the incidence of heart failure by 24% (19% to 28%) and calcium channel blockers by 19% (6% to 31%). CONCLUSIONS: With the exception of the extra protective effect of beta blockers given shortly after a myocardial infarction and the minor additional effect of calcium channel blockers in preventing stroke, all the classes of blood pressure lowering drugs have a similar effect in reducing CHD events and stroke for a given reduction in blood pressure so excluding material pleiotropic effects. The proportional reduction in cardiovascular disease events was the same or similar regardless of pretreatment blood pressure and the presence or absence of existing cardiovascular disease. Guidelines on the use of blood pressure lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure. Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.

Study design
Systematic review

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No.
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Randomized controlled clinical trials with at least 400 randomized patients were selected if at least one of the treatment arms used a CCB, ACEI, or ARB to evaluate stroke outcomes in hypertensive patients. DATA SYNTHESIS: The prevalence of stroke is high in the United States, accounting for approximately 150,000 deaths per year. Early identification and treatment of hypertension to quickly achieve blood pressure reduction is critical in the prevention of stroke. Many trials have provided evidence that CCBs, ACEIs, and ARBs are effective in stroke prevention. Most patients require two or more antihypertensive drugs to achieve blood pressure goals. Because of their complementary actions, combination antihypertensive therapy with a reninangiotensin-aldosterone system (RAAS) blocker and a CCB may help reduce stroke incidence to a greater extent than either of the monotherapies. CONCLUSION: A growing body of clinical trial data suggest that aggressive combination antihypertensive therapy, including a RAAS blocker and CCB, may help reduce stroke incidence. Fixed-dose combination therapy is an important consideration in optimizing blood pressure control and patient adherence to therapy in stroke prevention.consideration in optimizing blood pressure control and patient adherence to therapy in stroke prevention

Study design
Systematic review

Is this reference relevant to this recommendation (could be of use when considering updating this recommendation)?
Yes. Please go to question 2. No.
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How does this reference affects the existing recommendation?
Update of the recommendation needed (key reference). Please go to question 3.
Recommendation still valid (no update needed).
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3. Given the reference above, do any of the following issues around this recommendation need to be modified? (possibility of more than one answer) The population The intervention The comparison The outcome The quality of the evidence The direction of the recommendation Consistency of control of SBP is as important as extent of control (mean BP) in preventing stroke.

Study design
Systematic review

Is this reference relevant to this recommendation (could be of use when considering updating this recommendation)?
Yes. Please go to question 2. No.
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Update of the recommendation needed (key reference). Please go to question 3.
Recommendation still valid (no update needed).
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3. Given the reference above, do any of the following issues around this recommendation need to be modified? (possibility of more than one answer) The population The intervention The comparison The outcome The quality of the evidence

Abstract
Background: Randomized clinical trials have shown that thiazide-based regimens reduce vascular risk in persons with known stroke. Although presumed efficacious, the impact of non-diuretic-based antihypertensives on vascular outcomes after stroke has been less well studied and is not convincingly proven. Specifically the totality of evidence regarding efficacy of renin angiotensin system (RAS) modulators in individuals with prior stroke is unclear. We assessed the efficacy of RAS modulators in persons with a history of stroke by conducting a systematic review and meta-analysis. Methods: Systematic literature search was performed.
Inclusion criteria were 1) a randomized controlled trial; 2) participants with stroke history; 3) angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) as mandatory therapy in the active treatment group; 4) trials reporting cardiovascular events or just recurrent stroke as outcomes; 5) follow-up duration of at least 6 months. Studies were excluded if 1) mandatory ACE inhibitor or ARB used in control group; 2) additional treatment besides ACE inhibitor or ARB used in active group. Results: The search identified 7 randomized controlled trials comprising 28,805 participants with a history of stroke. Across all trials, RAS modulator therapy reduced cardiovascular events (relative risk 0.91, 95% confidence interval 0.86 to 0.96, P<0.001) (Fig 1). Across 6 trials with 25,791 participants with recurrent stroke reported as an endpoint, RAS modulator therapy marginally reduced stroke (relative risk 0.93, 95% CI confidence interval 0.86 to 1.00, P=0.05) (Fig 2). Heterogeneity existed between estimates of cardiovascular events (p<0.01, I<sup>2</sup> =65%) but not estimates of recurrent stroke (P<sup>2</sup>0.46, I<sup>2</sup> =0%). Conclusions: ACE inhibitor or ARB therapy modestly reduces the risk of future cardiovascular events in persons with a history of stroke. ACE inhibitor or ARB could be considered in patients with a history of stroke as add-on therapy, or in thiazide-intolerant patients. (Table presented) Study design Systematic review