血圧に対するココアの効果

一般的に血管に対して、ポリフェノールは効果的ですが、同時に入っている砂糖を取り過ぎたら意味がありません。

（※　管理者注）

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背景

高血圧は心血管疾患の重要なリスク因子の一つで、世界の心血管イベントの約50％、西洋諸国の心血管関連死の37％を占めている。疫学的研究では、ココア高含有製品により心血管疾患リスクが低減すると示唆されている。ココアで見出されたフラバノールは、血管拡張を促進し血圧を下げる内皮一酸化窒素の生成を増加すると示されている。以前のメタアナリシスでは、ココア高含有食品により血圧が低下すると示されている。最近の追加試験では相反した結果となっている。

目的

高血圧または高血圧でない参加者を対象に、フラバノール高含有チョコレートまたはココアが血圧に対する効果を検討すること。

検索方法

Cochrane Hypertension Group Specialised Register、CENTRAL、MEDLINE、EMBASEの電子的データベースを最初から2011年11月まで検索した。さらに、国際的試験登録簿、レビュー論文と選択した試験の参考文献リストを検索した。

選択基準

最低2週間成人を対象に収縮期と拡張期血圧に対するチョコレートまたはココア製品の効果を検討しているランダム化比較試験（RCT）。

データ収集と分析

2名のレビューアが別々にデータを抽出し、各試験のバイアスリスクを第三のレビューアと協議して評価した。Review Manager version 5.1およびStata version 12を用いて、選択基準を満たした全研究にランダム効果メタアナリシスを実施した。チョコレートまたはココア製品中のフラバノール（総または単量体）含有量、盲検化、ベースラインの血圧、テオブロミン含量、糖含量、体格指数（BMI）、投与期間、年齢などの変数によるサブグループ解析および単変量メタ回帰解析で異質性を探索した。

主な結果

20件の研究が選択基準を満たした。主に健康な参加者856名を対象とした20件の研究のメタアナリシスでは、2～18週間の短期間試験において、コントロールに比べてフラバノール高含有ココアの方が統計学的に有意に血圧を低下させたと示された。 収縮期血圧平均差（95%CI）、‐2.77（‐4.72～‐0.82） mmHg、p = 0.005、20件； 拡張期血圧平均差（95%CI）、‐ 2.20（‐3.46～‐0.93） mmHg、p = 0.006、拡張期血圧入手19件 試験では実介入群参加者に1日あたりココア製品3.6～105 gを投与していた。この中にはフラバノール30～1080 mg（平均545.5 mg）が含まれていた。試験の半数（10件）では、実投与群はフラバノール500～750 mg／日を摂取していた。コントロール群は、フラバノール無含有製品（12件）またはフラバノール低含有ココアパウダー（6.4および41 mgフラバノール、8件）の投与を受けた。フラバノール無含有コントロール群の試験のサブグループメタアナリシスでは、フラバノール低含有製品をコントロール群で用いた試験と対照的に有意な血圧低下効果がみられた。この解析は、試験期間および参加者盲検化の程度により交絡を受けている可能性があった。 試験期間は短期であった（平均4.4週間、範囲2～8週間、19件、1件は18週間）。2週間の期間の試験（9件）では有意な血圧低下効果が明らかであったが、2週間を超える試験（11件）では明らかではなかった。2週間の試験9件中7件（78％）がフラバノール無含有コントロール群を有していたことに注目することが重要である。したがって、期間によるサブグループ解析は、コントロール群で用いたフラバノールの用量と参加者の盲検化の程度により交絡を受けている可能性があった。 消化管愁訴および試験の製品の不快な味などの有害な作用は、ココア実投与群の5％、コントロール群の1％から報告された。

著者の結論

フラバノール高含有チョコレートおよびココア製品には、短期間で2～3 mmHgの小さいが統計学的に有意な血圧低下効果がある。

Cochrane Database of Systematic Reviews

Cochrane Systematic Review - Intervention Version published: 15 August 2012

https://doi.org/10.1002/14651858.CD008893.pub2

Karin Ried, Thomas R Sullivan, Peter Fakler, Oliver R Frank, Nigel P Stocks

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008893.pub2/full/ja

Background

High blood pressure is an important risk factor for cardiovascular disease attributing to about 50% of cardiovascular events worldwide and 37% of cardiovascular related deaths in Western populations. Epidemiological studies suggest that cocoa rich products reduce the risk of cardiovascular disease. Flavanols found in cocoa have been shown to increase the formation of endothelial nitric oxide which promotes vasodilation and therefore blood pressure reduction. Previous meta‐analyses have shown that cocoa‐rich foods may reduce blood pressure. Recently additional trials had conflicting results.

Objectives

To determine the effect of flavanol‐rich chocolate or cocoa products on blood pressure in people with or without hypertension.

Search methods

We searched the following electronic databases from inception to November 2011: Cochrane Hypertension Group Specialised Register, CENTRAL, MEDLINE and EMBASE. In addition we searched international trial registries, and the reference lists of review articles and included trials.

Selection criteria

Randomised controlled trials (RCT) investigating the effects of chocolate or cocoa products on systolic and diastolic blood pressure in adults for a minimum of two weeks duration.

Data collection and analysis

Two authors independently extracted data and assessed the risk of bias in each trial in consultation with a third author. Random effects meta‐analyses on all studies fitting the inclusion criteria were conducted using Review Manager version 5.1 and Stata version 12. Heterogeneity was explored by subgroup analyses and univariate meta‐regression analysis of several variables including dosage of flavanol content (total or monomers) in chocolate or cocoa products, blinding, baseline blood pressure, theobromine content, sugar content, body‐mass‐index (BMI), duration and age.

Main results

Twenty studies met the inclusion criteria. Meta‐analyses of the 20 studies involving 856 mainly healthy participants revealed a statistically significant blood pressure reducing effect of flavanol‐rich cocoa products compared with control in short‐term trials of 2‐18 weeks duration:

Mean difference SBP (95%CI): ‐2.77 (‐4.72, ‐0.82) mm Hg, p=0.005, n=20;

mean difference DBP (95%CI): ‐ 2.20 (‐3.46, ‐0.93) mm Hg, p=0.006, n=19 available for DBP.

Trials provided participants with 30‐1080 mg of flavanols (mean=545.5 mg) in 3.6‐105 g of cocoa products per day in the active intervention group. In half of the trials (n=10) the active group consumed 500‐750 mg of flavanols per day. The control group received either a flavanol‐free product (n=12) or a low‐flavanol containing cocoa powder (6.4 and 41 mg flavanols, n=8). Subgroup meta‐analysis of trials with a flavanol‐free control group revealed a significant blood pressure reducing effect, in contrast to trials using a low‐flavanol product in the control group. This analysis may have been confounded by trial duration and the level of blinding of participants.

Trial duration was short (mean 4.4 weeks, range 2‐8 weeks, n=19, and one trial of 18 weeks). A significant blood pressure reducing effect was evident in trials of 2 weeks duration (n=9), but not in trials of >2 weeks duration (n=11). It is important to note that seven out of the nine trials (78%) of 2 weeks duration also had a flavanol‐free control group. Therefore, subgroup analysis by duration might be confounded by flavanol dosage used in the control groups, and the level of blinding of participants.

Adverse effects including gastrointestinal complaints and distaste of the trial product were reported by 5% of patients in the active cocoa intervention group and 1% of patients in the control groups.

Authors' conclusions

Flavanol‐rich chocolate and cocoa products may have a small but statistically significant effect in lowering blood pressure by 2‐3 mm Hg in the short term.

Our findings are limited by the heterogeneity between trials, which was explored by univariate meta‐regression and subgroup analyses. Subgroup meta‐analysis of trials using a flavanol‐free control group revealed a significant blood pressure reducing effect of cocoa, whereas analysis of trials using a low‐flavanol control product did not. While it appears that shorter trials of 2 weeks duration were more effective, analysis may be confounded by type of control and unblinding of participants, as the majority of 2‐week trials also used a flavanol‐free control and unblinding of participants. Results of these and other subgroup analyses based on, for example, age of participants, should be interpreted with caution and need to be confirmed or refuted in trials using direct randomized comparison.

Long‐term trials investigating the effect of cocoa products are needed to determine whether or not blood pressure is reduced on a chronic basis by daily ingestion of cocoa. Furthermore, long‐term trials investigating the effect of cocoa on clinical outcomes are also needed to assess whether cocoa has an effect on cardiovascular events and to assess potential adverse effects associated with chronic ingestion of cocoa products.

Effect of cocoa on blood pressure

Flavanols found in cocoa have been associated with blood pressure lowering properties due to their stimulation of nitric oxide dependent vasodilation. In this review we assessed the effect of cocoa products on blood pressure in adults when consumed daily for a minimum of two weeks.

Meta‐analysis of 20 studies involving 856 mainly healthy participants revealed a small but statistically significant blood pressure reducing effect of ‐2.8 mm Hg systolic and ‐2.2 mm Hg diastolic.

Trials were of short duration, all but one trial were between two and eight weeks long (n=1 of 18 weeks). While a significant effect with trials of two weeks duration (n=9) was evident, it was not with trials of longer duration (n=11). It is not clear whether this result is directly attributable to the trial length or may be due to another factor such as the type of control group used in the shorter trials or the level of blinding of participants to the treatment. While analysis of trials using a flavanol free control group indicated a significant effect on blood pressure, analysis of trials using a low flavanol control group did not.

Adverse effects including gastrointestinal complaints and distaste of the trial product were reported by 5% of patients in the active cocoa intervention group and 1% of patients in the control groups.

Although we did further analyses and explored other subgroups for an effect (including by age, body mass index and baseline blood pressure; sugar content of the cocoa product), the results of all subgroup analyses, and any measured association of effect, need to be tested, and confirmed or refuted, in further trials.

The small reduction in blood pressure of about 2‐3 mm Hg observed in the pooled trials overall might complement other treatment options and might contribute to reducing the risk of cardiovascular disease. However, we were unable to identify any randomized, controlled trials that tested the effect of long‐term daily ingestion of cocoa products on blood pressure and there were no trials that measured an effect on clinical outcomes related to high blood pressure such as heart attacks or strokes.

More trials in which the intake of low flavanol dosages are compared with flavanol‐free controls are required to test whether low dosages are effective in reducing blood pressure. In addition, longer term trials are needed to elucidate whether regular consumption of flavanol‐rich cocoa products has a beneficial effect on blood pressure and cardiovascular health over time, and whether there are any potential adverse effects of long‐term ingestion of cocoa products on a daily basis.

Authors' conclusions

Implications for practice

Our review suggests flavanol‐rich chocolate and cocoa products to have a small but statistically significant effect in lowering blood pressure by 2‐3 mm Hg.

Trials were generally of short duration (n=19: range 2‐8 weeks, one of 18 weeks), and the majority was conducted in healthy individuals (n=18). Participants consumed 3.6‐105 g of cocoa products per day containing 30‐1080 mg of flavanols (mean=545.5 mg).

Analysis of trials using a flavanol‐free control group revealed a significant blood pressure reducing effect of cocoa, whereas analysis of trials using a low‐flavanol product as the control did not. While it appears that shorter trials of two weeks duration were more effective, analysis may be confounded by type of control and unblinding of participants, as the majority of two‐week trials also used a flavanol‐free control and participants were unblinded. It is possible that small doses of flavanol‐rich cocoa products have a beneficial effect on blood pressure, and trials using low‐dose flavanol products as a control may have attenuated any effect between intervention and control groups.

The reduction in blood pressure of about 2‐3 mm Hg might complement other treatment options and might contribute to reducing the risk of cardiovascular disease.

Implications for research

Randomised double‐blind placebo‐controlled trials with a flavanol‐free control group are needed to eliminate a potential effect of daily low‐dose cocoa flavanol intake on blood pressure in the control group.

Trials designed to directly compare the effect of cocoa in different age groups, and the effect of sugar content in cocoa products in patients with BMI > 25 are needed to test the findings of our subgroup analyses.

Tracking of blood pressure over a longer than two week period would assist with the assessment of any accumulative effects over time and should evaluate tolerability and acceptability.

Long‐term trials investigating the effect of cocoa on clinical outcomes are needed to assess whether cocoa has an effect on cardiovascular events.

Background

Dark chocolate and flavanol‐rich cocoa products have attracted interest as an alternative treatment option for hypertension, a known risk factor for cardiovascular disease. Even small reductions in blood pressure substantially reduce cardiovascular risk. Current guidelines strongly recommend integration of lifestyle modification and complementary treatment with the use of conventional blood pressure medications.

The interest in the effect of cocoa on blood pressure started with the discovery that an island population in Central America, the Kuna Indians had a distinctively low rate of hypertension coupled with a consistent healthy low blood pressure unaffected by age (Hollenberg 2006, Kean 1944). The majority of the Kuna Indians live on the San Blas Island off Panama (population approx. 35,000); those Kuna Indians who migrated to the mainland manifest a higher prevalence of hypertension as well as an age‐dependent rise of blood pressure, implying that lifestyle factors such as diet rather than genetics play a protective role (McCullough 2006). Island‐dwelling Kuna Indians consume about 3‐4 cups of cocoa drinks on average per day, while the mainland‐dwelling Kuna Indians consume up to 10 times less cocoa (McCullough 2006, Schroeter 2006). Average high salt intake was not associated with the differences in blood pressure (McCullough 2006). Mean blood pressure of the island‐dwelling adult Kuna Indians hovers around 110 mm Hg systolic and 70 mm Hg diastolic, while on the mainland observed age‐related blood pressure rise and hypertension prevalence is comparable to that of Western populations (Hollenberg 2006).

High blood pressure is a critically important risk factor for cardiovascular disease, attributable for 47% of ischemic heart disease and 54% of stroke events worldwide (Lawes 2008). More than a third (37%) of cardiovascular deaths are attributed to hypertension in Western populations (Martiniuk 2007) and 13.5% globally (Lawes 2008). The association between cardiovascular risk and blood pressure levels are continuous (McInnes 2005) with the risk of ischemic heart disease and stroke halved for every 20 mm Hg reduction in systolic blood pressure (SBP) and 10 mm Hg diastolic blood pressure (DBP) (Lewington 2002). Even small reductions in blood pressure therefore can substantially reduce cardiovascular events at a population level.

Cocoa is extracted from cacao beans, the fatty seeds of the Theobroma cacao tree. Cocoa is rich in flavanols, particularly epicatechin, catechin and procyanidins, proposed to be responsible for the blood pressure lowering effect (Corti 2009, Heiss 2010a). Flavanols are also found in other plant‐derived produce, including beans, apricots, blackberries, apples and tea leaves, albeit in a lower concentration than in cocoa products (460‐610 mg/kg of flavanol monomers; 4‐5 g/kg of flavanol polymers) (Fernandez‐Murga 2011, Hammerstone 2000). Flavanol intake is, however, also dependent on serving size, and flavanol content depends on the processing of the cacao beans and raw cocoa.

Traditionally cocoa was consumed as a cold unsweetened drink of raw dried cacao powder, often mixed with starch and spices by the native Indians, but this was considered bitter and unpalatable for the early European explorers, including Christopher Columbus in 1502 and Hernando Cortes in 1519. The Spanish brought cocoa to Europe, to which sugar was added and the drink was heated (Lippi 2009, Dillinger 2000). Subsequent roasting (up to 120 °C), mixing (conching), alkalising (dutching), adding sugar, milk, vanilla and lecithin emulsifiers make chocolate as we know it today (Beckett 2008). Various chocolate manufacturers have fine‐tuned the processing leading to different flavours and smoothness of chocolates, but also to altered cocoa and flavanol content in various cocoa products.

Dark chocolate contains larger amounts of cocoa (50‐85%) than milk chocolate (20‐30%). Different processing procedures however influence the flavanol content of the cocoa in the chocolate; a 70% cocoa containing chocolate bar from one company therefore might not contain the same amount of flavanols and flavanol composition as a 70% chocolate bar from another company. Content and composition of flavanols depend on the variety and ripeness of cocoa beans used as well as the manufacturing steps.

Fresh and fermented cocoa beans contain about 10% of flavanols (100 mg/g), the cocoa powder consumed by the Kuna Indians contains about 3.6% of flavanols, and cocoa‐rich dark chocolate on the market about 0.5 % of flavanols (Chevaux 2001, Chaitman 2006). Moreover, heavy dutching, the alkalising of chocolate to pH 7‐8, can reduce the flavanol content to less than 10 mg per 100 g (0.001 %).

Furthermore, research suggests that the monomeric portion of cocoa flavanols, epicatechin and catechin and to a lesser extend the polymeric flavanols, the procyanidins, are linked to blood pressure and vasoactive effects (Schroeter 2006). Modern processing of cacao reduces the monomeric flavanol content and influences the epicatechin/catechin ratio (Payne 2010). Fresh and fermented cocoa beans contain between 2.5 to 16.5 mg of epicatechin per gram depending on the variety, the growing region and harvesting practices (Kim 1984, Wollgast 2000), whereas processed cocoa retains only 2‐18% of the original epicatechin, due to roasting and dutching (Payne 2010).

Due to the large variation in flavanol content in chocolate and cocoa products, it is critical to compare the dosages of flavanols rather than simply the amounts of chocolate or administered cocoa products in clinical trials investigating the effect of cocoa on blood pressure.

Description of the condition

Primary hypertension: systolic blood pressure (SBP) ≥ 140 or diastolic blood pressure (DBP) ≥ 90 mm Hg.

Prehypertension: SBP 120‐139 or DBP 80‐89 mm Hg.

Normotension: SBP < 120 or DBP < 80 mm Hg, secondary hypertension.

Description of the intervention

Flavanol‐rich chocolate and cocoa products compared with control (low‐flavanol products or placebo) consumed on a daily basis for two weeks or more.

How the intervention might work

The blood pressure lowering properties of cocoa have been linked to the formation of endothelial nitric oxide (NO) which promotes vasodilation and consequently lowers blood pressure. Increased NO production might be triggered by upregulation of NO‐synthase through the insulin‐mediated signalling pathway (Addison 2008). Insulin sensitivity was shown to be improved after cocoa intake in a number of trials (Davison 2008a; Grassi 2005a; Grassi 2008; Faridi 2008), but not in one (Muniyappa 2008). Secondly, cocoa flavanols have been shown to inhibit angiotensin converting enzyme (ACE) activity, and hence reduce blood pressure (Actis‐Goretta 2006, Persson 2011). Thirdly, there is evidence to suggest cocoa flavanols to have an indirect antioxidant effect within the cardiovascular system, upregulating NO‐synthase activity and hence reducing blood pressure (Keen 2005, Fraga 2011).

Why it is important to do this review

In the last decade, several clinical trials have investigated the effect of chocolate and cocoa products on blood pressure. This systematic review updates previous meta‐analyses by Taubert 2007a (including 5 trials), Desch 2010a (10 trials), and Ried 2010(15 trials). In addition, we explored the influence of baseline blood pressure, flavanol dosage, duration, type of control, study design, age, body mass index, and trial quality on blood pressure outcome.

Objectives

To assess the effects of chocolate or cocoa products versus low‐flavanol products or placebo on blood pressure in adults with or without hypertension when consumed for 2 weeks or longer.

Discussion

Summary of main results

Our meta‐analysis suggests chocolate or cocoa products to be more effective in reducing blood pressure compared with control:

Mean difference SBP (95%CI): ‐2.77 (‐4.72, ‐0.82) mm Hg, p=0.005, n=20;

mean difference DBP (95%CI): ‐ 2.20 (‐3.46, ‐0.93) mm Hg, p=0.0006, n=19.

Trials were generally of short duration (n=19: range 2‐8 weeks, one of 18 weeks) and the majority was conducted in healthy individuals. Heterogeneity was generally high. We explored reasons for heterogeneity in the following subgroup analyses.

Meta‐analysis of trials with flavanol‐free control groups revealed a significant blood pressure reducing effect, while no significant effect was found when pooling trials using a low‐flavanol product in the control group.

It is plausible that any differences found between the treatment and control groups were weakened in trials using high‐flavanol versus low‐flavanol products, as the low‐flavanol product may also have an effect on blood pressure. In fact, trials studying acute effects reported a sustained accumulative effect on vascular function when flavanols were taken daily over 1 or 3 weeks (Heiss 2007, Balzer 2008). In addition, one trial included in our review provided a small amount of daily dark versus white chocolate (6.3 g) over a 4‐month period and reported a cumulative effect on blood pressure at 6, 12 to 18 weeks, respectively (Taubert 2007): mean SBP (SD) difference of ‐0.5 (1.6), ‐2.0 (1.7), ‐2.8 (1.6) mm Hg; and mean DBP (SD) difference of ‐0.4 (1.5), ‐1.6 (1.0), ‐1.9 (1.5) mm Hg.

Subgroup meta‐analyses by baseline blood pressure revealed a more pronounced effect of cocoa in systolic hypertension,compared with systolic prehypertension or normotension. However, a differentiation into those groups was not supported by meta‐regression and test for subgroup differences. A significant blood pressure lowering effect of cocoa was evident in diastolic blood pressure independent of status at baseline.

It has been suggested that theobromine found in cocoa might be indicative for vasoactivity and thus blood pressure reduction of cocoa products (Kelly 2005) However, we did not find an association between theobromine content in cocoa and blood pressure. Theobromine is the bitter alkaloid of the cacao plant, and also found in other plants, such as tea and the cola nut. Other similar compounds, the methylxanthines include caffeine in coffee.

It is questionable whether the chocolate and cocoa products are palatable if large amounts of the bitter theobromine are included. In addition, very high dosages of theobromine might have side effects in humans. While some animals, such as dogs, might succumb to theobromine poisoning from as little as 50 g of chocolate for a smaller dog and 400 g for an average‐sized dog due to slow metabolism of theobromine (Strachan 1994), it is estimated that a 60 kg human would need to consume about 4.5 kg of dark chocolate with natural containing theobromine to be poisoned (Rusconi 2010). However, theobromine‐enriched cocoa powder containing about 30 times more theobromine than commercial chocolate has been used in small quantities in a trial included in this review (Bogaard 2010). Adverse effects of such theobromine‐enriched cocoa might be expected by intake of only 150 grams.

We found a larger beneficial effect of cocoa on blood pressure if the test products contained only low amounts of sugar (< 10 g/day). The beneficial effect of cocoa products with low sugar content was even more pronounced in overweight and obese individuals ( BMI > 25). A high sugar load might reduce micro‐ and macrocirculation in the arteries due to acute hyperglycemia (Akbari 1998).

While we did not identify Body Mass Index (BMI) to be a predicting variable for the effect of cocoa on blood pressure, if viewed in combination with sugar intake the differences in effect could be explained by an increased insulin‐resistance often associated with higher BMI. Fat accumulation in skeletal muscle disrupts the insulin‐mediated signalling pathway, causing higher levels of insulin and elevation of blood pressure (Addison 2008).

While we found a difference in the effect of 2‐week long trials compared with longer trials, it is possible that this subgroup analysis by duration was confounded by the fact that the majority of trials with a flavanol‐free control group were also of two weeks duration. Furthermore, several 2‐week trials asked participants to consume a large amount of chocolate per day (1 bar = 100 g). This might be impractical in the long‐term and might cause some unwanted side effects such as weight gain. Therefore, while shorter term trials appear more effective, meta‐analysis results by duration should be interpreted cautiously.

We found cocoa to be more effective in reducing blood pressure in younger individuals (mean age range 18‐45.4 yrs) in the short term trials compared with older individuals (mean age range 51‐69.7 yrs). The age‐ related effect might be associated with the structural and biochemical changes in the arterial wall apparent with aging (O'Rourke 1990) and subsequent vascular reactivity to stimuli. Age‐related changes include arterial stiffening in association with decrease of elastin, and increase of collagen and glycosaminglycans (O'Rourke 1990). In addition, endothelin‐1, a potent vasoconstrictor protein is elevated in older adults (Donato 2009) and endothelial oxidative stress compromising NO availability is more pronounced in the elderly (Taddei 2001). Cocoa flavanols have been shown to reduce vascular resistance, arterial stiffness, endothelin‐1 and are potent scavengers of free radicals (Schroeter 2006, Loke 2008) leading to improved vascular function.

In the short‐term studies included in our review, the effect of cocoa on blood pressure might be more pronounced in younger individuals due to the age‐related decrease of vascular reactivity to physiological stimuli such as cocoa flavanols.

Overall completeness and applicability of evidence

Data were available for the majority of identified trials fitting the inclusion criteria (n=20). Two trials were excluded due to lack of data (Balzer 2008; Farouque 2006). Most trials studied healthy subjects with or without elevated blood pressure (n=18). One trial (Heiss 2010) included subjects with coronary artery disease, and one trial assessed individuals with impaired glucose tolerance (Grassi 2008). Therefore, our findings are applicable largely to healthy adults with or without hypertension. Our review included all types of cocoa products. Six out of 20 included trials did not report on epicatechin content of the cocoa product, and six out of 20 did not report on theobromine content, therefore limiting conclusions of meta‐regression analysis of these two variables.

Our meta‐analysis contributes to the evidence of flavanol‐rich cocoa products to benefit cardiovascular health, albeit the effect of cocoa on blood pressure overall appears to be modest. No long‐term trials investigating the effect of cocoa products on clinical outcomes are available to draw conclusions on the effect of cocoa on cardiovascular events or long‐term adverse effects.

Quality of the evidence

A sufficient number of trials (n=20) and a reasonably large sample size (n=856) was available to generate meaningful meta‐analysis and allowed several subgroup analyses. Subgroup analyses were supported by meta‐regression analyses and explored heterogeneity. Due to high heterogeneity, insufficient evidence on adequate allocation concealment in 55% of trials, single‐blinding in 45% of trials, and some publication bias, the quality of the evidence is considered low (summary of findings Table for the main comparison). Further research is very likely to have an important impact on our confidence in the estimate of the effect and is likely to change the estimate. However, remaining high heterogeneity in selected subgroups was reduced considerably by exclusion of one trial (Grassi 2005b), therefore increasing robustness of results. Sensitivity analyses excluding Grassi 2005b did not change effect sizes appreciably.

Subgroup analyses by age, BMI, and hypertension status at baseline might be subject to ecological bias. The effect found between studies might not hold within studies. However, individual patient data was not available.

Potential biases in the review process

A strength of this review is the comprehensive literature search including several databases, trial registries and reference lists of included trials. While we were able to obtain unpublished data from authors of three trials for inclusion, we had to exclude two trials due to lack of data. We followed the Cochrane Handbook for analysis of the data.

Agreements and disagreements with other studies or reviews

Our meta‐analysis suggests chocolate or cocoa products to be more effective in reducing blood pressure compared with control:

Mean difference SBP (95%CI): ‐2.77 (‐4.72, ‐0.82) mm Hg, p=0.005, n=20;

mean difference DBP (95%CI): ‐ 2.20 (‐3.46, ‐0.93) mm Hg, p=0.006, n=19 available for DBP.

Albeit significant, the reduction in systolic blood pressure weakened with increasing number of studies compared to previous meta‐analyses:

a) Ried 2010 (15 trials): mean difference SBP (95%CI): ‐3.16 (‐5.08, ‐1.23) mm Hg, p=0.001;

b) Desch 2010a (10 trials): mean difference SBP (95%CI): ‐4.52 (‐5.87, ‐3.16) mm Hg, p<001; and

c) Taubert 2007a (5 trials): mean difference SBP (95%CI): ‐4.7 (‐7.6, ‐1.8) mm Hg, p=0.002.

Overall reduction in diastolic blood pressure in our updated meta‐analysis is also a little smaller than reported in earlier meta‐analyses:

a) Ried 2010 (15 trials): mean difference DBP (95%CI): ‐2.02 (‐3.35, 0.69) mm Hg, p=0.003;

b) Desch 2010a (10 trials): mean difference DBP (95%CI): ‐2.5 (‐3.9, 1.2) mm Hg, p<0.001; and

c) Taubert 2007a (5 trials): mean difference DBP (95% CI): ‐2.8 (‐4.8, ‐0.8) mm Hg, p=0.006.