Antiplatlet Effects of Standardized Tomato Extract in Hypertensive Subjects
Condition: Hypertension,Essential; Obesity
MeSH terms: Essential Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      The reducing the anti-aggregation properties of platelets significantly decreases the risk of
      myocardial infarction and the total number of cardiovascular events. In patients who have
      cardiovascular disease, anti-platelet therapy reduces the risk of serious vascular events.
      Side effects, such as bleeding, are relatively small so the benefits of anti-platelet therapy
      in secondary prevention exceed the risk of these side effects. According to guidelines for
      the treatment of arterial hypertension, PTNT 2015, patients with arterial hypertension (HA)
      that have a 20% or higher risk for cardiovascular events in the next 10 years, should have
      ASA included in their treatment to reduce this risk. It has been proved that the use of
      acetylsalicylic acid in secondary prevention reduces the risk of major cardiovascular events,
      while the benefits of ASA in primary prevention have recently been debated. The benefits of
      using ASA in primary prevention should always be confronted with the risk of hemorrhagic
      complications of this therapy According to 2016 European Guidelines on cardiovascular disease
      (CVD) prevention in clinical practice, anti-platelet therapy is not recommended in
      individuals who do not suffer from CVD, due to the increased risk of major bleeding. It is
      important to look for alternative anti-platelet therapy for people with cardiovascular risk
      factors. Standardized tomato extract (STE) does not cause side effects and may have multiple
      beneficial effects on total cardiovascular risk, primarily by inhibiting platelet
      aggregation. Since its discovery in 1999, several studies and human trials with STE have been
      carried out. During the last 50 years, tomato (Lycopersicon esculentum) has become a highly
      consumed food. The benefits of inhibiting platelet activity through diet are currently
      difficult to determine due to the lack of clear and comprehensive scientific data. It is
      difficult to specify the over activity of the plaques or their proper activity. However,
      there are data available that indicate the benefits of a diet containing diminishing activity
      of platelets (Mediterranean diet) and lowering cardiovascular risk.The investigators want to
      conduct a comparison of the less common STE with clinically recognized ASA. The aim of the
      study was to compare the anti-platelet effect of STE and ASA in hypertensive patients with
      high cardiovascular risk.The study highlights that STE may be an alternative, food-based
      strategy to control the platelets reactivity.
    

Detailed description: 
      Study design The study involved 82 high-risk hypertensive patients (44 men and 38 women),
      aged 28-74years, conducted between July 2015 and February 2017 in the Department of
      Hypertension at the University of Medical Sciences in Poznan. Seventeen patients reported
      resignation during the study. The permission no. 377/15 to conduct the study was published by
      the Ethics Committee at the Poznan University of Medical Sciences. All the patients gave
      informed consent for participation in the study. Patients with primary hypertension and high
      cardiovascular risk were randomly assigned to one of two groups. Group 1(ASA) included 33
      patients who received acetylsalicylic acid at a dose of 75 mg in the morning. Group 2 (STE)
      included 32 patients receiving standardized tomato extract (STE) (ZAAX, Sequia, Poland) at a
      dose of 213 mg orally in the morning.

      The patients had two visits within 4 weeks according to the scheme:

      Visit 1: During the first visit, patients were qualified for the study. The patients with
      previously diagnosed hypertension were referred from an outpatient clinic, to the hospital
      ward. After admission, the patients with high cardiovascular risk were isolated and written
      consents were obtained.

      On the basis of stage of hypertension, presence of risk factors and subclinical organ damage,
      diabetes coexistence, cardiovascular complications and chronic kidney disease the
      cardiovascular risk was estimated. Each patient with one or two risk factors and a blood
      pressure (BP) > 180/110 mmHg or three or more risk factors, and a BP >160/100 mmHg or with
      the presence of organ damage and BP >140/90 mmHg were classified as a high risk Group.There
      have been no changes in the concomitant treatment (lipid-lowering, anti-hypertensive and
      antidiabetic) during the study.

      Numerous laboratory tests and imaging, such as aldosterone and ARO levels, both before and
      after tilting, creatinine, urea, GFR, sodium, potassium, pro BNP, TSH, FT3, FT4, and a
      24-hour collection for electrolytes were collected. Abdominal ultrasound examinations,
      computed tomography of the abdomen, and Doppler ultrasound of the renal arteries were
      performed to exclude secondary causes of hypertension. Clinical BP measurements were
      performed three times, as well as, ambulatory blood pressure monitoring (ABPM) and
      echocardiography was conducted. Whole blood samples were taken and baseline platelet
      aggregation was determined using the VerifyNow analyzer from Accumetrics. In Group 1, two
      whole blood samples for VerifyNow Aspirin test were assayed. In Group 2, four whole blood
      samples for VerifyNow Aspirin and P2Y12 tests were assayed.

      Visit 2: After 4 weeks of taking STE or ASA the patients visited the hospital for the second
      visit. All examinations from visit 1, including platelet aggregation inhibition assays, were
      repeated. Whole blood samples were collected 1-4 h after the ingestion of a morning ASA or
      STE dose from a peripheral vein using a 21 gauge or larger needle in a partial fill 3.2%
      citrate vacuum collection tube.

      Standarized tomato extract characteristics STE is a water-soluble tomato concentrate, free of
      lycopene and fats, which contains 37 biologically active compounds of well-known structure.
      These bioactive compounds contain nucleosides (adenosine, cytidine, guanosine, inosine, AMP,
      GMP), polyphenols including flavonoids (rutin, quercetin, kemferol, luteoline, naryngenin)
      and phenolic acids (chlorogenic, coffee, p-coumar, ferulic).

      In 2009, the European Food Safety Authority (EFSA) approved the water soluble tomato
      concentrate (WSTC) as a food supplement which helps to maintain normal platelet aggregation.
      EFSA recommended the use of STE in healthy individuals between 35 and 70. The effective daily
      dose was 3 g of bioactive compounds contained in syrup or 65-150 mg in powdered form.

      This extract affects the inhibition of ADP-mediated aggregation, thromboxane, collagen, von
      Willebrand factor, thrombin and inflammatory mediators. What is more, it blocks the P2Y12
      receptor for ADP and limits intracellular granular release of thromboxane, ADP, selectin P
      and factor 4 (PF4, platelet factor 4). Additionally, it prevents activation of αIIbβIII
      integrin and inhibits (GP) IIb / IIIa receptor activation. By inhibiting the P2Y12 receptor
      for ADP, it increases cAMP activity and this results in decreasing intracellular calcium ions
      concentration. Inhibition of collagen binding process with GP VI as well as von Willebrand
      factor with GP Ib receptor and decrease in Cβ and Cy2 phospholipase activity are also
      included in anti-aggregation effects of STE. These phenomena affect the shape of thrombocytha
      and are reversible while maintaining a level of platelet activity that allows aggregation in
      case of vascular injury. ZAAX can be used by people with hypersensitivity to salicylates and
      other non-steroidal anti-inflammatory drugs, with bronchial asthma, with active peptic
      ulceration.

      Studies have shown that STE inhibits the activation of endothelial inflammatory processes,
      which prevents the development of atherosclerosis. STE reduces the production of inflammatory
      cytokines (TNF-α, IL-1β and IL-12) and to increases the synthesis of interleukin 10, which
      has anti-inflammatory properties.

      VerifyNow® Tests Procedure The study protocol included measurements of platelet reactivity
      using a VerifyNow Tests Procedure (Accumetrics Inc., USA). This method detects platelet
      activity by measurement of platelet aggregation, in a blood sample, exposed to a specific
      agonist. This leads to an inhibition of platelet function in response to anti-platelet
      therapy. The VerifyNow System is a whole blood device that performs qualitative measurement
      of induced platelet aggregation based on the increase in light transmittance. Two types of
      VerifyNow test kits were used in the study: VerifyNow Aspirin Test and VerifyNow P2Y12. The
      Aspirin test results are reported as Aspirin Reaction Units (ARU), which are calculated as a
      function of the rate of aggregation. ARU values less than 550 indicate effective result of
      ASA, while values > 550 ARU indicate no effect of the drug. The VerifyNow P2Y12 test measures
      platelet function based on the ability of activated platelets to bind fibrinogen and provides
      information on the aggravation of platelet aggregation in reactivity units of P2Y12 receptor
      (PRU). It is considered that the range of 95 - 208 PRU is responsible for optimal
      antiplatelet activity. High PRU values after drug administration, point to the lack of
      expected anti-platelet effect.

      Blood pressure measurements In all the patients, during each visit, BP measurements were
      performed three times at rest, in the supine position, in standard conditions, and using an
      upper arm blood pressure monitor (Omron 705IT). Ambulatory, 24-hour blood pressure
      measurements (ABPM) were carried out using an A&D, 24-hour ambulatory peripheral blood
      pressure monitor. The frequency of measurements was every 15 minutes between 7:00 and 22:00
      and every 30 minutes between 22:00 and 7:00.

      Statistical analysis Statistical analyses were performed with Statistica, version 12.5.
      (StatSoft, USA). Since the tested data did not meet the assumption of Gaussian distribution
      (evaluated with Shapiro-Wilk method), the non-parametric methods were applied. The Wilcoxon
      signed-rank test was used for evaluation of the differences between the initial values and
      the values obtained after the treatment, for factors of; body weight composition, blood
      pressure, and platelet aggregation. To evaluate differences and correlations between the two
      independent groups the Mann-Whitney U test and Spearman׳s rank correlation coefficient (Rs)
      were used, respectively. The data presented on graphs and tables included median and
      interquartile ranges. A p<0.05 was considered as significant.
    

Intervention name(s): acetylsalicylic acid; Tomato Fruit Extract
Intervention type(s): Drug; Drug
Intervention description(s): Group 1(ASA) included 33 patients who received acetylsalicylic acid at a dose of 75 mg in the morning; Group 2 (STE) included 32 patients receiving standardized tomato extract (STE) (ZAAX, Sequia, Poland) at a dose of 213 mg orally in the morning
Other intervention name(s): Group 1 ASA; Group 2 STE
Intervention MeSH terms: Aspirin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: standardized tomato extract; anti-aggregation; high cardiovascular risk; diet supplement