Background
Hypertension is a major risk factor for cardiovascular disease. In everyday practice, elevated blood pressure (and accompanying symptoms with less regular control) is often the first reason to seek medical advice. High blood pressure fluctuations can also be one of the first symptoms of ischemic heart disease. During the diagnostic process, the overall condition of the patient should be assessed and possible earlier undisclosed comorbidities identified (these include lipid disorders, diabetes, thyroid, hyperuricemia, etc.). It is important to assess the carotid arteries, i.e., the thickness of the intima-media complex (IMT) and the presence or absence of atherosclerotic lesions.
Absolute risk of death from cardiovascular complications in 10 years according to the Systematic COronary Risk Evaluation (SCORE) scale should be estimated, and any modifiable risk factors that can be changed should be identified [1]. However, the basis for the SCORE scale is to assess only 5 risk factors - smoking, high systolic blood pressure, cholesterol, gender and age (40-65 years) - which restricts its comprehensive application. Risk assessment should be repeated at 5-year intervals. According to the European Society of Cardiology (ESC) guidelines for cardiovascular disease prevention, the presence of asymptomatic target organ damage predicts the probability of death from cardiovascular complications, irrespective of the SCORE scale results. Clinical data inclusion increases the accuracy for the prediction of actual risk, especially in people with low to moderate risk according to the SCORE scale (1-4% 10-year risk SCORE scale) [1].
The guidelines of the European Society of Hypertension (ESH) include risk score scales from earlier guidelines divided into small, moderate, large and very large, relating to a 10-year risk of cardiovascular death in accordance with the definitions from the ESC guidelines on prevention [1]. This evaluation should consider gender and age (men ≥55 years, women ≥65 years), smoking, lipid disorders (chol >190 mg/dL, LDL-Ch >115 mg/dL, HDL-Ch <40 mg/dL and <45 mg/dL for women, triglycerides >150 mg/dL), fasting blood glucose levels (102-125 mg/dL), abnormal glucose tolerance test results, obesity (BMI ≥30 kg/m2), abdominal obesity (waist circumference: for white race men ≥102 cm, women ≥88 cm), premature occurrence of cardiovascular disease in the family history (men <55 years, in women <65 years), asymptomatic organ damage, diabetes, cardiovascular disease or none [1,2]. In the light of the above recommendations, besides optimal blood pressure control, coexisting disorders affecting the cardiovascular risk should be effectively treated.
Mechanisms of thrombotic complications in hypertension
Hypertension is an important risk factor of atherothrombosis development. An additional cardiovascular risk of thromboembolic complications in hypertensive patients may be partly due to an imbalance between prothrombotic and fibrinolytic factors in the blood circulation. Its cause is mainly due to increased shear stress and renin-angiotensin-aldosterone (RAA) system pathological activation, especially angiotensin-converting enzyme (ACE) and angiotensin II (ANG II). A prothrombotic state in arterial hypertension and left ventricular hypertrophy increase the risk of ischemic stroke eightfold and heart infarction fourfold. The fibrinolytic system is one of the defense mechanisms for the prevention of intravascular thrombosis. Important components are protein anticoagulants (antithrombin III, protein C and S, heparin cofactor II) and short-acting, endothelial platelet inhibitors – nitric oxide (NO) and prostacyclin [3]. Hemostatic risk factors in arterial hypertension are: plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (t-PA), fibrinogen, von Willebrand factor (vWF), thrombomodulin, blood platelets, P-selectin and factor VII. In hypertensive patients, plasma fibrinolytic activity is decreased due to increased PAI-1 and lower concentrations of tissue plasminogen activator (t-PA).Elevated activity and the concentration of the PAI-1 antigen may indicate high-risk individuals. There is a PAI-1 levels peak in the early morning, while the afternoon fall in plasma PAI-1 corresponds with a peak in endogenous fibrinolysis.Quantification of plasma levels of t-PA antigen may reflect the endothelium function, whereas t-PA activity has an effect on fibrinolytic properties. In the Framingham Offspring Population study, linear regression models that were used to evaluate systolic and diastolic blood pressure as predictors of fibrinolytic and hemostatic factor levels in separate gender models, with adjustment for age, body mass index, smoking, diabetes, total cholesterol, HDL, triglycerides, alcohol intake and estrogen use, demonstrated that in both sexes the levels of PAI-1 and t-PA antigen were positively related to systolic and diastolic blood pressure (p<0.001) [4]. Blocking the RAA axis results in the lowering of PAI-1 concentration and activity as well as increased production of t-PA. T-PA is found in several forms, including free forms and forms bound to PAI-1. The rise in t-PA activity is related to bradykinin increase which is the most potent stimulus of endothelial t-PA synthesis. Therefore, ACE inhibitors (ACE-I) augment t-PA actions. The effects of angiotensin receptor blockers (ARB) on fibrinolysis are not as obvious because receptor subtypes other than AT1 mediate the effect of ANG II on endothelial PAI-1 expression, i.e., the AT4 receptors. ACE-I and ARB also have different effects on insulin sensitivity: ACE-I improves insulin sensitivity, while the majority of ARB have a neutral effect. ARB do not affect the metabolism of bradykinin, which stimulates t-PA synthesis and release [5].
Arterial hypertension is also associated with reduced clot permeability, impaired clot lysability and faster fibrin formation in plasma-based assays. Effective antihypertensive treatment may be associated with increased clot permeability and more efficient clot lysis following six months of therapy. This effect is correlated with a reduction in systolic blood pressure. Other factors, such as von Willebrand factor (vWF) and F1+2, play an important role in the fibrinolysis system; however, there have not been many studies in hypertensive patients. Increased plasma level of vWF is frequently present in hypertensive patients and this has been seen as a marker of endothelial dysfunction [6]. In the ASCOT study, vWF in hypertensive patients was significantly elevated in comparison to normotensives (138 vs. 98 IU/dL, p<0.001) but, after six months of effective intensified blood pressure lowering and hypercholesterolemia treatment, it was seen to decrease significantly [6,7]. Increased vWF concentration in hypertensive patients is a marker of endothelial dysfunction and has a prognostic value for stroke and acute coronary syndromes.
Excessive activation of aldosterone also causes additional prothrombotic effects. Pathogenic effects of aldosterone are the result of mineralocorticoid-receptor activation which activates signaling pathways and synthesis of PAI-1, active oxygen radicals and pro-inflammatory cytokines. Increased sensitivity to vasoconstriction substances and reduction of NO synthesis can occur. The inhibitory effect of these changes on fibrinolysis is significant. Fibrinogen, an acute phase protein, is also an independent risk factor for cardiovascular disease in the general population, especially in patients with arterial hypertension. The concentrations of fibrinogen correlate with the severity of organ damage and atherosclerosis. In patients with hypertension, a high concentration of fibrinogen is the result of inflammation due to damage to the endothelium.
Blood platelets are activated in arterial hypertension by shear stress, higher catecholamine levels, atherosclerotic lesions, higher activity of the RAA system and increased blood viscosity. Platelet changes may be morphological (volume, shape, half-life), biochemical (receptors, catecholamine, serotonin, calcium concentrations) and functional (increased aggregation, adhesion, degranulation). All these processes increase the risk of cardiovascular complications.
In conclusion, a prothrombotic state in hypertensive patients is primarily characterized by high fibrinogen concentrations, fibrinolysis attenuation and platelet activation. Its severity depends on the degree of endothelial dysfunction, organ damage and concomitant atherosclerotic lesions.
Impact of antihypertensive drugs on the fibrinolytic system
Experimental and clinical studies have shown that ACE-I induce a reduction of PAI-1 levels in patients with hypertension, coronary heart disease and heart failure. The positive effect of ACE-I on the fibrinolytic system has been related to inhibition of angiotensin II, inhibition of bradykinin degradation and improvement of insulin sensitivity [8]. ACE-I can be divided into tissue-specific (zofenopril, ramipril, perindopril, quinapril, benazepril, fosinopril) or serum ACE inhibitors (captopril, enalapril, lisinopril). More than 90% of ACE are located in the vascular endothelium, within the vessel walls and in organs such as the lungs, kidneys, adrenals, brain and heart, but only 10% in the serum.
Tissue fraction of ANG II is located in the walls of blood vessels and regulates homeostasis of many organs, causing local but long-term vascular adverse effects. Serum fraction plays an important role in fluid, electrolyte homeostasis and blood pressure regulation. Evidence from clinical comparative studies implied the advantage of profibrinolytic action of tissue ACE-I. It has been reported that both activity and plasma concentrations of PAI-1 are lowered by several ACE inhibitors.
In the FACTS trial, the higher hypotensive power ofamlodipine in comparison to fosinopril was associated with a tendency to increase PAI-1, in contrast to fosinopril that tended to decrease its value. Changes in PAI-1 concentrations depended on the drug dosage [20]. A beneficial effect of benzapril therapy on PAI-1 activity was also observed. Another study involving outpatients with mild to moderate hypertension and well controlled type 2 diabetes mellitus showed that the mean pre-treatment PAI-1 values significantly decreased after perindopril, but not after losartan therapy. Differential fibrinolytic activity between the pre- and post-cilazapril treatment was detected, possibly due to the plasminogen activators released from the endothelium, which may have been stimulated by ACE-I. In another study, cilazapril had a beneficial effect on the lipid profile and on fibrinogen, but its combination with a diuretic drug reversed this effect. In addition, perindopril, losartan and valsartan exerted antiplatelet activity at rest and following acute exercise in patients with essential hypertension [9]. Data on the influence of beta-blocker therapy on fibrinolytic parameters in hypertensive patients are inconsistent. Sayer et al showed that metoprolol was only able to flatten the circadian pattern of PAI-1 antigen but had no significant influence on its baseline values [10]. Vyssoulis et al studied 550 consecutive patients with uncomplicated essential hypertension who were treated with celiprolol, carvedilol or nebivolol monotherapy and achieved comparable blood pressure reduction. After six months of treatment, nebivolol and celiprolol reduced PAI-1 antigen concentrations, whereas carvedilol had no statistically significant effect [11]. Results of the ASCOT study raised the questions concerning the safety of beta-blocker and diuretic therapy in hypertension [12]. Diuretic treatment is still regarded as a mainstay of antihypertensive therapy, although little is known as to how it works or if it may change fibrinolytic activity [13].
Antiplatelet drugs in hypertension
Acetylsalicylic acid (ASA) or clopidogrel treatment in patients without cardiovascular disease, including cerebrovascular diseases, is not recommended in primary prevention according to current ESC standards due to the increased risk of major bleeding (class of recommendation IIIB) [1,14]. This was confirmed by the ESC and ESH recommendations (2013): ASA is not recommended for the prevention of cardiovascular disease in patients with hypertension with low or moderate risk of cardiovascular complications in whom the benefits and cardiovascular risks are equivalent (class of recommendation IIIA) [2]. In previously healthy men and women with low risk, risk reduction of cardiovascular events after treatment with ASA is small and should be assessed against the background of increased risk of serious bleeding [15]. Therefore, any decision on ASA administration in primary prevention should be taken individually. ASA is not recommended for use in the general population. Generally, the ESC recommends the use of aspirin in patients with a 10-year CVD risk of >20%. The decision on ASA administration in men and women whose 10-year risk of coronary heart disease exceeds 10% should be carefully considered [2]. Antiplatelet therapy should be initiated after obtaining full control of blood pressure. According to Cochrane Quality and Productivity topics, ASA cannot be recommended for the primary prevention of cardiovascular events in patients with hypertension because the benefit does not outweigh the damage which may occur. The increase in benefit is, however, much greater for secondary prevention, so ASA is recommended for this indication [16].
On the other hand, antiplatelet therapy should always be considered in patients with hypertension who have had a cardiovascular event (secondary prevention), with high cardiovascular risk including accompanying diabetes and chronic kidney disease. This was confirmed by the results of the subgroup analysis of the HOT study: a significant benefit in terms of reducing cardiovascular events occurred in patients with a GFR <45 mL/min/1.73 m2 [17]. In patients receiving antiplatelet therapy, attention should be paid to the increased risk of bleeding, particularly gastrointestinal bleeding [1,2]. In the near future, ongoing trials in high risk populations such as the ASPirin in Reducing Events in the Elderly (ASPREE), A Study of Cardiovascular Events iN Diabetes (ASCEND), and Aspirin to Reduce the Risk of Vascular Events (ARRIVE) will provide us with more clinical data on the subject of ASA usage.
ASA resistance is another clinical issue, occurring in an average of 30% of patients [18]. The alternative drug may be clopidogrel, but its role deserves further investigation. Glycoprotein P2Y12 inhibitors, ticlopidine and clopidogrel are not recommended in the primary prevention of cardiovascular events in patients with hypertension. Proof of the effectiveness of this treatment is lacking and the risk of hemorrhagic complications is substantial [15]. Clopidogrel is recommended in secondary prevention in patients after ischemic stroke, and in those patients with peripheral arterial or multivascular disease as well as after myocardial infarction (in the case of ASA intolerance). Also, dipyridamole should not be used in primary prevention of cardiovascular complications in essential hypertension. Treatment should be considered in patients with or without ASA intolerance in the secondary prevention of ischemic stroke or transient ischemic attacks (TIA) [16].
Anticoagulation therapy in patients with arterial hypertension
Warfarin is not recommended in the primary prevention of cardiovascular events in patients with hypertension. There is no evidence on the effectiveness of such therapy and the risk of hemorrhagic complications is substantial [16]. The risk of bleeding is significantly higher when any of the following exists: a previous history of bleeding, a patient’s age of over 75 years, uncontrolled hypertension, and concomitanttreatment with non-steroidal anti-inflammatory drugs (NSAIDs) or with additional concomitant medications. There is no sufficient clinical evidence to support the use of anticoagulant drugs in hypertensive patients [15].
Arterial hypertension is a significant risk factor of atrial fibrillation (AF) and is diagnosed in about 70% of patients with AF. Using the CHA2DS2-VASc and HAS-BLED stroke and bleeding risk stratifications scoring systems ischemic stroke and bleeding risk can be established. In CHA2DS2-VASc, stroke risk factors include: arterial hypertension, congestive heart failure (or left ventricular dysfunction), age ≥75 years, diabetes mellitus, prior stroke, TIA or thromboembolic disease, vascular disease, age 65-74 years and gender (i.e., female). HAS-BLED includes bleeding risk factors: arterial hypertension, abnormal renal and liver function, history of stroke and bleeding, labile INRs, older age, drugs (NSAIDs, antiplatelet drugs) or alcohol usage [19, 20]. So arterial hypertension is simultaneously a risk factor of stroke and bleeding in patients with AF (equal to one “risk” point in each these different scoring systems). Consequently, the decision about whether to employ an anticoagulant drug should be consider individually in each patient with arterial hypertension and AF.
Conclusion
Arterial hypertension is, per se, a prothrombotic state. Among hypertensive drugs, only ACE inhibitors may have a fibrinolytic potential. At present, preventive treatment with antiplatelet and anticoagulant drugs in low-risk hypertensive patients is not recommended. According to current guidelines, decisions concerning antithrombotic therapy should be based on individual patient risk of cardiovascular complications. In the future, the results of ongoing trials will perhaps establish more definite recommendations for clinical practice in this area.
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