Vitamin D supplementation for preventing recurrent stroke and vascular events in patients with stroke or transient ischaemic attack

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

Primary objective

To study the effect of vitamin D supplementation alone or in combination with calcium, for preventing recurrent stroke (fatal or non‐fatal) among patients with a prior history of stroke or TIA.

Secondary objective

To assess the effect of vitamin D supplementation with or without calcium for the prevention of composite vascular events (stroke, MI, PAD and death from vascular cause) and all‐cause mortality, in patients with a prior history of stroke or TIA.

Background

Description of the condition

Stroke is the most common cause of disability and a leading cause of mortality worldwide, with approximately 5.54 million deaths per year (WHO Report 2000). Recurrent strokes account for around 30% of all stroke events (Goldstein 2006).

Almost one billion people in the world suffer from vitamin D deficiency or insufficiency. Traditionally, vitamin D has been associated primarily with bone health (Holick 2007), but emerging data indicate that vitamin D deficiency plays an important role in the genesis of vascular risk factors (Holick 2007; Zittermann 2006). Hypovitaminosis D has been independently associated with increased rates of stroke, implicated in almost 75% of patients presenting with acute stroke (Poole 2006). It has also been associated with other serious vascular events such as myocardial infarction (MI) (Wang 2008), and related mortality; along with hypertension (Forman 2007), type II diabetes mellitus (Knekt 2008) and peripheral arterial disease (PAD) (Melamed 2008).

Mechanistically, endothelial dysfunction is the ultimate cause of atherosclerotic vascular disease (Widlansky 2003) and an independent predictor of future events. It is this common pathway that vitamin D appears to influence. There is evidence to suggest that vitamin D is an independent factor in endothelial stabilisation, and may also be able to reduce hypertension (Lind 1988; Pfeifer 2001; Witham 2009). A recent trial conducted among patients with a history of stroke and low vitamin D levels (less than 75 nmol/L) reported that a single oral dose of 100,000 units of vitamin D2 significantly improved endothelial function at eight weeks (6.9% versus 3.7%; adjusted P = 0.007) and led to reduced blood pressure (BP) levels in hypertensive patients (mean BP greater than 140 mmHg). However, there was no significant change at 16 weeks and normotensive patients did not incur a significant change in BP (Witham 2010). Another trial, carried out among type II diabetic patients using a similar dose of vitamin D, showed an improvement in endothelial function, with a reduction in BP by 8 to 13 mmHg (Sugden 2008). Vitamin D may be involved not only in initiating atherosclerotic vascular injury but also in plaque progression, since early signs of atherosclerosis such as increased carotid intima‐media wall thickness have been implicated with low vitamin D levels (Doherty 1997; Targher 2003).

There is evidence to suggest that vitamin D supplementation in patients with low baseline levels may reduce risk of serious vascular events (Pilz 2011). A number of clinical trials and meta‐analyses have shown that vitamin D supplementation in moderate to high doses reduces the risk of cardiovascular disease (Autier 2007; Wang 2010). However, there are no meta‐analyses evaluating vitamin D supplementation as a secondary preventive measure for recurrent stroke or transient ischaemic attack (TIA).

Description of the intervention

Vitamin D is a fat‐soluble vitamin that is present in fatty fish, cheese and beef liver. It is also produced when ultraviolet rays from sunlight strike the skin. Vitamin D is biologically inert and must undergo two hydroxylations in the body for activation. The first occurs in the liver and converts vitamin D to 25‐hydroxyvitamin D (25(OH)D), also known as calcidiol. The second occurs primarily in the kidneys and forms the physiologically active 1,25‐dihydroxyvitamin D (1,25(OH)2D), also known as calcitriol.

Vitamin D increases absorption of calcium from the small bowel. Without vitamin D, only 10% to 15% of dietary calcium is absorbed (Deluca 2004). The interaction of 1,25‐dihydroxyvitamin D with the vitamin D receptor increases the efficiency of intestinal calcium absorption to 30% to 40% (Heaney 2003). Calcium may yield its benefits in other body systems by reducing BP and improving lipid profile. It is postulated that both vitamin D and calcium may interact to provide greater improvement in health status. However, calcium supplements alone have proven to accelerate vascular calcification (Block 2007; Goodman 2000). A recent meta‐analysis on the effect of calcium supplementation without vitamin D showed that calcium supplements were associated with about a 30% increase in the incidence of MI and smaller, non‐significant, increases in the risk of stroke and all‐cause mortality. The results were similar for recurrent cardiovascular events and stroke (Bolland 2010). Therefore, we will evaluate data regarding the effect of combined vitamin D and calcium supplementation on recurrent stroke against that of vitamin D or calcium alone. We will also assess the safety profile of combined vitamin D and calcium against that of vitamin D or calcium alone in these respective studies.

How the intervention might work

Most tissues in the body, including the brain and immune cells, have a vitamin D receptor and respond to 1,25‐dihydroxyvitamin D (D3), the active form of vitamin D. Recent studies have indicated that D3 is a potent inducer of trophic factors. It augments the expression of glial cell line‐derived neurotrophic factor (GDNF) and transforming growth factor (TGF) in the neural cells which protect against brain ischaemia by preventing the release of excitatory amino acids and nitric oxide, and reducing free radical generation. Since vitamin D3 is able to cross the blood‐brain barrier, it is possible that systemic administration of this compound can protect against Ischaemic brain injury indirectly via an elevation of neurotrophic factors (Wang 2000).

There are several other mechanisms by which vitamin D can prevent recurrent cerebrovascular events. Vitamin D supplementation improves endothelial function by decreasing vascular resistance (Norman 2005; Sugden 2008). It has been shown to reduce levels of tumour necrosis factor‐α (TNF‐ α), one of the pro‐inflammatory cytokines in atherosclerosis (Schleithoff 2006). Vitamin D also reduces activation of macrophages, a key cellular component of the atherosclerotic response (Sadeghi 2006). Human endothelial cells are able to synthesize the active form of vitamin D, which may act at the local level to modulate the effects of inflammatory cytokines on the vasculature (Zehnder 2002).

The main marker of vitamin D status is serum or plasma 25‐hydroxyvitamin D (25‐(OH)D). A very high proportion of patients who have suffered a stroke have low 25‐(OH)D levels.  A recent study from the American Heart Association showed that low levels of 25‐(OH)D and 1,25‐(OH)2D are independently predictive for fatal strokes (Pilz 2008). Apart from reducing the risks of osteopenia, fractures and falls; vitamin D supplementation also exerts antithrombotic and neuroprotective effects and has also shown to attenuate ischaemic cortical injury in rats (Aihara 2004). Another study comparing 44 elderly patients admitted with a first acute stroke with 96 elderly controls found that 25‐(OH)D levels were significantly lower in cases than controls (P < 0.0001) with the majority (77%) of stroke patients having vitamin D deficiency that preceded the stroke (Poole 2006). Hence, there is a strong link established between hypovitaminosis and cerebrovascular events.

Why it is important to do this review

A number of randomised controlled trials (RCTs) and meta‐analyses have documented association between low 25‐(OH)D levels and systolic blood pressure, type II diabetes mellitus, risk for cardiovascular disease, and mortality. No evidence‐based review exists regarding the effects of vitamin D supplementation on prevention of stroke recurrence.

Stroke is a major public health problem particularly in developing countries. Review of the results of RCTs is required to determine if vitamin D supplementation can prevent the recurrence of stroke. If vitamin D is shown to protect against this outcome, it can be made available at very low costs in populations of middle and low income groups, where deficiency is very common (Masood 2008). Our aim is to specifically look at the effect of vitamin D supplementation with and without calcium on recurrent stroke and composite vascular events in patients with stroke or TIA.

Objectives

Primary objective

To study the effect of vitamin D supplementation alone or in combination with calcium, for preventing recurrent stroke (fatal or non‐fatal) among patients with a prior history of stroke or TIA.

Secondary objective

To assess the effect of vitamin D supplementation with or without calcium for the prevention of composite vascular events (stroke, MI, PAD and death from vascular cause) and all‐cause mortality, in patients with a prior history of stroke or TIA.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs in which participants with a prior history of stroke or TIA were given vitamin D supplementation (D2/D3, oral or intramuscular form with or without calcium supplementation) for a minimum of one month.

Types of participants

All male and female adults over 18 years of age with a history of stroke or TIA who received vitamin D with or without calcium supplementation for ≤ 30 days .  We will consider the definition of TIA at the time of the publication of the article.

Types of interventions

The intervention is any dose of vitamin D (either cholecalciferol or ergocalciferol) oral or intramuscular, given alone or in combination with calcium. Any dose of vitamin D (either cholecalciferol or ergocalciferol), oral or intramuscular, given alone or in combination with calcium compared with placebo, no treatment or calcium alone. To avoid potential confounding, if the control group is receiving calcium then we will include studies that compare vitamin D plus calcium versus calcium alone.

Types of outcome measures

Primary outcomes

These will be recurrent strokes (fatal or non‐fatal). Recurrent stroke is defined as any stroke that is reported during the study period after the study intervention has been administered.

Secondary outcomes

These will be the composite vascular outcome (stroke, MI, PAD or death from vascular causes) and all‐cause mortality.

Search methods for identification of studies

See the 'Specialized register' section in the Cochrane Stroke Group module.

Electronic searches

We will search the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), MEDLINE (from 1948) (Appendix 1), EMBASE (from 1980), CINAHL (from 1982) and AMED (Allied and Complementary Medicine Database, from 1985).

We developed the MEDLINE search strategy with the help of the Cochrane Stroke Group Trials Search Co‐ordinator and will adapt it for the other databases.

Using a comprehensive search strategy the Cochrane Stroke Group Trials Search Co‐ordinator has already completed a retrospective search of MEDLINE and EMBASE for all stroke trials to January 2008 and added all relevant trials to the Stroke Group Trials Register. To avoid duplication of effort we have limited the search of these two databases from January 2008 onwards.

Searching other resources

In an effort to identify further published, unpublished and ongoing trials we will:

1. search the following ongoing trials registers:

   1. ClinicalTrials.gov (http://www.clinicaltrials.gov/);

   2. EU Clinical Trials Register (https://www.clinicaltrialsregister.eu);

   3. Stroke Trials Registry (www.strokecenter.org/trials/);

   4. Current Controlled Trials (www.controlled‐trials.com);

   5. WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/);

2. search the reference lists of identified studies and reviews;

3. contact authors and experts in the field;

4. use Science Citation Index Cited Reference Search for forward tracking of important articles.

We will search for relevant trials in all languages and arrange translation of trial reports published in languages other than English.

Data collection and analysis

We will review all studies that fit the inclusion criteria. The inclusion criteria for studies are:

• clinical trials with random allocation of participants into two or more treatment groups, including a control or placebo group;

• vitamin D administered alone or in combination with calcium;

• information on recurrent cerebrovascular events (fatal and non‐fatal) during follow‐up.

We will contact study authors for data on outcome measures not reported in their articles.

Selection of studies

Two authors will independently screen the titles and abstracts of all reports identified from the searches of the electronic bibliographic databases and exclude obviously irrelevant records. We will obtain the full text of the remaining studies and the same two authors will select those trials meeting the inclusion criteria. They will not be blinded to the names of authors, institutions, journals and results when they make the eligibility decision. They will resolve any disagreements through discussion and if necessary we will consult two other authors who will act as arbiters. Two authors will independently screen the titles and abstracts of all reports for eligibility against the inclusion criteria by two authors, with two other authors acting as arbiters when there is no consensus. They will not be blinded to the names of authors, institutions, journals and results when they make the eligibility decision.

Data extraction and management

We will design a specific questionnaire for data extraction, which will include information to identify the source of data, eligibility, methods (including sequence generation and allocation), details of participants (including age, gender and ethnicity), latitude, interventions (dose and type of vitamin D, cholecalciferol or ergocalciferol), outcomes (primary and secondary) and results. Two authors will independently extract data from each study. We will resolve any differences in data extraction by discussion.

Assessment of risk of bias in included studies

Two authors will independently assess each study for risk of bias using the Cochrane Collaboration's tool for assessing risk of bias as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and extracting information on sequence generation; allocation concealment; blinding of participants, personnel and outcome assessors; the degree of incomplete outcome data (from withdrawals); and selective reporting of outcomes.

Measures of treatment effect

We will use risk ratio (RR) with 95% confidence intervals (CI) to measure treatment effects for dichotomous data. We will extract actual data of outcome events and number of people randomised in each trial to calculate pooled RRs for each outcome.

Unit of analysis issues

For studies where there is more than one follow‐up period, we will select the longest period to extract outcome data. This will maximize the statistical power of our meta‐analysis. For non‐fatal events, we will only record the first event for each participant.

Dealing with missing data

We will contact authors from all identified trials to request information on the primary outcomes. During data extraction, we will record the amount of missing data for outcome variables. If this is substantial (> 20%) we will assume the missing data showed no benefit from the given vitamin D and perform sensitivity analyses to assess the effect of this assumption on summary rate ratios.

Assessment of heterogeneity

We will assess the presence of any possible heterogeneity statistically using the I² statistic, with a value above 50% indicating heterogeneity. We will examine the contribution of individual studies to heterogeneity by calculating the I² statistic with each study removed from the analysis.

Assessment of reporting biases

If possible, we will use funnel plots to assess the possible presence of publication bias.

Data synthesis

We will used a random‐effects model. For dichotomous data, which is what we have as our primary and secondary outcome measures, we will present results as a summary of RR with 95% CI.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses will include:

• low versus high vitamin D levels (less than 50 nmol/L versus more than 50 nmol/L);

• low versus high vitamin D supplementation (< 800 IU versus > 800 IU daily);

• vitamin D combined with calcium versus vitamin D alone;

• demographic status (age, gender);

• by risk factor profile (diabetes mellitus, hypertension, elevated lipids, PAD);

• by ethnicity/race.

Sensitivity analysis

We will carry out sensitivity analyses if there are studies with variable follow‐up periods or with substantial missing data. We will analyse the data without the studies that have substantial missing data to assess the robustness of the pooled risk ratios. Sensitivity analyses will be on studies using the same TIA definition. We will perform sensitivity analyses on latitude and forms of vitamin D based on the available studies.

Appendices

Appendix 1. MEDLINE (Ovid) search strategy

1. cerebrovascular disorders/ or exp basal ganglia cerebrovascular disease/ or exp brain ischemia/ or exp carotid artery diseases/ or exp cerebrovascular trauma/ or exp intracranial arterial diseases/ or exp intracranial arteriovenous malformations/ or exp "intracranial embolism and thrombosis"/ or exp intracranial hemorrhages/ or stroke/ or exp brain infarction/ or vasospasm, intracranial/ 2. (stroke or poststroke or post‐stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or SAH).tw. 3. ((brain$ or cerebr$ or cerebell$ or intracran$ or intracerebral) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$)).tw. 4. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracranial or subarachnoid) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw. 5. ((transi$ adj3 isch?em$ adj3 attack$) or TIA$1).tw. 6. 1 or 2 or 3 or 4 or 5 7. vitamin d/ or exp cholecalciferol/ or exp ergocalciferols/ 8. (vitamin D or vitamin D2 or vitamin D3).tw. 9. Vitamin D Deficiency/ or hypovitaminosis D*.tw 10. (alfacalcidol or AT‐10 or atocalcitol or becocalcidiol or calcamine).tw,nm. 11. (calcifediol or calcidiol or calciferol or calciol or calcipotriol or calcitriol).tw,nm. 12. (calderol or cholecalciferol$ or colecalciferol or dedrogyl or didehydrocalcitriol or dihydrotachysterol or dihydroxycolecalciferol).tw,nm. 13. (dihydroxycholecalciferol or dihydroxyvitamin D or doxercalciferol or ecalcidene or eldecalcitol or elocalcitol or epicalcitriol or ercalcidiol).tw,nm. 14. (ergocalciferol$ or falecalcitriol or hidroferol or hydroxycalciferol or hydroxyl‐calciferol or hydroxycolecalciferol or hydroxycholecalciferol).tw,nm. 15. (hydroxyergocalciferol$ or hydroxyvitamin D or hydroxyl‐vitamin D or inecalcitol or lexacalcitol or oxacalcitriol or paricalcitol or seocalcitol).tw,nm. 16. (sitocalciferol or tachystin or tisocalcitate).tw,nm. 17. or/7‐16 18. 6 and 17 19. Randomized Controlled Trials as Topic/ 20. random allocation/ 21. Controlled Clinical Trials as Topic/ 22. control groups/ 23. clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or clinical trials, phase iv as topic/ 24. double‐blind method/ 25. single‐blind method/ 26. Placebos/ 27. placebo effect/ 28. Drug Evaluation/ 29. Research Design/ 30. randomized controlled trial.pt. 31. controlled clinical trial.pt. 32. (clinical trial or clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv).pt. 33. random$.tw. 34. (controlled adj5 (trial$ or stud$)).tw. 35. (clinical$ adj5 trial$).tw or trial.ti 36. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw. 37. (quasi‐random$ or quasi random$ or pseudo‐random$ or pseudo random$).tw. 38. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw. 39. placebo$.tw. 40. controls.tw. 41. or/19‐40 42. 18 and 41 43. exp animals/ not humans.sh. 44. 42 not 43

What's new

Last assessed as up‐to‐date: 12 January 2012.

Date	Event	Description
23 February 2017	Amended	Withdrawn

Contributions of authors

AKK conceived the review and was involved in editing the protocol. FM drafted the protocol. IN was involved in writing and editing the protocol.

Declarations of interest

None known.

Notes

This protocol has been published since 2012. It has been withdrawn from publication because the authors have been unable to complete the full review and the protocol is now out of date.

Withdrawn from publication for reasons stated in the review