Effects of Valsartan and Aliskiren on Hemostatic Indices in Hypertensive Diabetics
Effects of Valsartan and Aliskiren on Hemostatic Indices in Hypertensive Diabetics
People with both hypertension and diabetes have a higher chance of developing heart and
 arterial problems that could be reduced with anti-coagulant therapy. Valsartan (Diovan), an
 FDA approved angiotensin-II receptor antagonist (blocker) clinically indicated for the
 treatment of essential hypertension is known to inhibit platelet activity in both an in vitro
 and ex vivo setting. Aliskiren (Tekturna) is a recently FDA-approved potent direct renin
 inhibitor which is also an effective anti-hypertensive agent in patients with
 mild-to-moderate hypertension and which, in vitro, modulates antithrombin III in plasma.
 Therefore, in addition to being clinically approved anti-hypertensive medications, combining
 these two agents will potentially target both primary hemostasis (platelets) and
 anticoagulant (antithrombin-III is a cornerstone substrate for heparin) properties to exert
 their anti-thrombotic efficacy simultaneously. This combination strategy may not only improve
 hypertension management, but also improve vascular outcomes in high-risk diabetic population
 via favorable effects on anti-thrombotic activity. Importantly, there have been no
 significant additional safety concerns of using the combination of aliskiren and valsartan.
 The investigators hypothesis is that valsartan 160 mg/daily in combination with aliskiren
 150-300 mg/daily for 4 weeks will favorably affect blood levels of
 platelet/coagulation/fibrinolytic biomarkers (ie, diminish platelet activity, and enhance
 antithrombin III potency) when compared with monotherapy with aliskiren 150mg/daily in
 hypertensive patients with type 2 diabetes mellitus.
Objectives:

 There are 2 objectives in the index study. • The primary objective is to determine how
 therapy with valsartan (160mg/daily) in combination with aliskiren (150-300mg/daily) over
 four weeks affects platelet/coagulation/fibrinolytic biomarkers in recently diagnosed
 hypertensive patients with type 2 diabetes mellitus. However, this is an exploratory study,
 our current knowledge is based on in vitro and ex vivo evidence for valsartan, but only on in
 vitro aliskiren data. There are no data on antithrombotic biomarkers currently available for
 the combination therapy.

 The secondary objective is:

 • To define whether combination therapy is superior over monotherapy with aliskiren with
 regard to the improvement of hemostatic biomarkers (platelet aggregation, expression of GP
 IIb/IIIa, and plasma levels of antithrombin-III).

 Study Design:

 This is a randomized 1:1, two arm, single-blind, single-site, parallel group, post-marketing
 comparison study of the effects on antithrombotic biomarkers of aliskiren 150-300mg/day alone
 vs combined treatment with aliskiren 150-300mg/day plus valsartan 160mg/day over a four week
 primary treatment period. An optional four week extension phase may be offered pending
 assessment of the antithrombotic biomarker assays at week four.

 Population:

 Two groups (25 patients each), for a total of 50, recently diagnosed hypertensive patients
 with previously diagnosed mild to moderate type 2 diabetes will constitute the proposed study
 population. The diagnosis of diabetes will be made based on the American Diabetes Association
 criteria, such as random plasma glucose >200 mg/dL with or without symptoms of hyperglycemia
 (polydipsia, polyuria, polyphagia) and weight loss, or fasting plasma glucose > 126 mg/dL, to
 be determined at least twice. Patients will qualify if they are insulin-free, treated with an
 oral antiglycemic agent,(metformin only) and/or managed on diet alone for no less than 30
 days and have adequate glucose control at the time of their Screening Visit.
Inclusion Criteria:

 1. The diagnosis of Type 2 Diabetes Mellitus will have been determined by the following
 Criteria, as characterized by recurrent or persistent hyperglycemia, and diagnosed by
 demonstrating any one of the following.

 -  Fasting plasma glucose level at or above 126 mg/dL but less than 250 mg/dL on
 more than one determination.

 -  Plasma glucose at or above 200 mg/dL two hours after a 75 g oral glucose load as
 in a glucose tolerance test.

 -  Symptoms of hyperglycemia and casual plasma glucose at or above 200 mg/dL.

 -  Glycated hemoglobin (hemoglobin A1C) at or above 6.5 but below 8.5%. (This
 criterion was recommended by the American Diabetes Association in 2010).

 2. Adults between 21 - 65 years old

 3. Have been diagnosed with Type 2 DM according to the criteria listed above, and treated
 with metformin 1-2 g/daily as their only diabetic medication, and/or an approved ADA
 diet for no less than 30 days.

 4. Documented evidence of Stage 1 or Stage 2 essential hypertension as noted below:
 However, the actual treatment threshold will be left to the discretion of the study
 investigators.

 Stage 1: systolic 140-159 mmHg and diastolic 90-99 mmHg Stage 2: systolic >160 mmHg
 and diastolic >100 mmHg However, there is accumulated evidence that patients with
 consistent blood pressures over 130/80 mmHg along with Type 1 or Type 2 diabetes, or
 kidney disease are at increased risk for progressive morbidity and mortality and
 require a lower threshold for further treatment.

 5. Aspirin 81 mg/daily

 6. Signed informed consent

 7. Must maintain same diet/exercise regimen

 Exclusion Criteria:

 1. Thrombolytic therapy, GP IIb/IIIa inhibitor, thienopyridines, antifibrinolytics, COX-
 inhibitors, prostacyclin analogues, and vitamin K antagonists within 30 days of
 enrollment

 2. Platelet count < 100,000/microL

 3. History of bleeding disorder

 4. Hct < 30%, serum creatinine ≥3 mg/dL, liver impairment defined as ALT/AST > 3 times
 upper limit of normal.

 5. Glomerular filtration rate <60ml/min/1.73m2

 6. Patients currently treated with any antiplatelet agent other than aspirin 81 mg/day

 7. Admission for acute vascular syndrome (unstable angina, MI, stroke), revascularization
 procedure with stent placement, or other major coronary/cerebrovascular event within
 30 days.

 8. Active participation in other investigational drug or device trial within the last 30
 days.

 9. Allergy or intolerance to any of the study medications.

 10. Congestive Heart Failure (NYHA I-IV)

 11. Malignancies except treated non-melanoma superficial skin cancers

 12. Acute infections

 13. Type I diabetes, Cushings syndrome, or pancreatic deficiency due to malignancy or
 systemic disease

 14. Insulin therapy, sulfonylureas, thiazolidinediones,meglitinides, D-phenylalanine
 derivatives, amylin synthetic derivatives, and incretin mimetics.

 15. Pregnancy, confirmed by serum rosette inhibition assay for early pregnancy factor
 detectable. For women of child-bearing potential (WOCP), continuous abstinence,
 fertility awareness, hormonal contraceptives, and/or mechanical methods will apply to
 prevent pregnancy during the entire study duration. Should a subject become pregnant
 during the study, the anti-hypertensive treatment with either or both study
 medications will be discontinued immediately by the treating physician/investigator as
 per FDA warnings regarding potential fetal/neonatal morbidity and mortality.

 16. Age over 65 years

 17. History of cigarette smoking within past 10 years