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.