© Springer International Publishing Switzerland 2017Tulio Pinho Navarro, Alan Dardik, Daniela Junqueira and Ligia Cisneros (eds.)Vascular Diseases for the Non-Specialist10.1007/978-3-319-46059-8_19
19. Clinical Treatment of Vascular Diseases
Cirurgia Vascular, SHIS QI 29 Conj 12 CS 09, Lago Sul, Brasilia, 71675-320, Brazil
Joice Cristina Daltoé Inglez
Clinical treatment of vascular disease holds several pathologies and their risk factors. The most important are arterial obstructive disease, aortic aneurysm, and acute aortic syndrome.
Obstructive vascular disease reaches all arterial territories, with atherosclerosis as the most important cause. In peripheral artery disease, obstruction of limb arteries will determine the presence of symptoms, such as intermittent claudication and critical limb ischemia (rest pain, gangrene, or ulcers). Clinical management of obstructive disease includes control of risk factors and symptomatic relief, prevention of cardiovascular events and improvement of functional capacity.
The aortic aneurysm and acute aortic syndrome are complex pathologies of aorta. The main goal of medical therapy in aortic aneurysm and acute aortic syndrome is to decrease shear stress on aortic wall (thus reducing rupture and growing rates) and inflammation process since there is a direct relation between diameter, grown and rupture rates.
KeywordsMedical treatmentClinical managementPeripheral artery diseaseClaudicationCritical limb ischemiaRisk factorsAortic aneurysmAortic dissectionAcute aortic syndromeDyslipidemiaAntiplateletAntihypertensive
Obstructive vascular disease is widespread in all arterial territories, reaching cardiovascular, intracranial, and peripheral arteries [1–6]. Prevalence of peripheral artery disease reaches 30 % in patients >70 years although 2/3 are asymptomatic; patients with peripheral artery disease have a larger risk of all-cause and vascular-cause of death [3, 4, 7–10]. In peripheral artery disease, obstruction of limb arteries and limited blood flow will determine the presence of symptoms, such as intermittent claudication and critical limb ischemia (rest pain, gangrene, or ulcers) [6, 9, 10]. Critical limb ischemia is the most severe manifestation of the disease and holds elevated cardiovascular and limb morbidity and mortality [11, 12].
Atherosclerosis is the leading cause of obstructive disease, and all territories share the same risk factors, such as male gender, smoking, hypertension, hyperlipidemia, diabetes mellitus, and chronic kidney disease [2–5, 13]. Other risk factors related to peripheral disease are the presence of elevated blood levels of inflammation markers (high-sensitivity C-reactive protein), thrombosis factors (homocysteine levels, fibrinogen), and elevated lipoproteins [2, 7]. Low HDL (high density cholesterol) is a major predictor for cardiovascular event [3, 14].
The main goals of treatment are:
control of the risk factors (involves antiplatelet, antihypertensives, and statins)
prevent cardiovascular (CV) events
improve function capacity
Guidelines recommend to calculate cardiovascular risk score in order to predict cardiovascular events in a long period of time [2, 15]. It is based on age, gender, smoking, hyperlipidemia, and blood pressure . There are many risk scores available, such as Framingham, SCORE (Systemic Coronary Risk Estimation) , ASSIGN (CV risk estimation model from the Scottish Intercollegiate Guidelines Network), Q-Risk, PROCAM (Prospective Cardiovascular Munster Study) , and WHO (World Health Organization) . The Framingham and SCORE are the most used .
The assessment of risk allows to categorize the patient’s risk, to identify who will benefit from prevention therapies, and to keep strict surveillance on those with high cardiovascular risk [2, 15, 16]. Once risk factors are continuous, there is no specific threshold to achieve and patients should be reevaluated every 3–5 years if CV risk <5 % and every year if CV risk ≥5 % [2, 15–18].
Categories of Cardiovascular Risk
There are four categories of risk:
Very high risk : Greater than 10 % risk for fatal atherosclerotic events such as coronary infarction, stroke, or other obstructive arterial event in 10 years. This group includes all patients with documented atherosclerotic disease, type 2 diabetes mellitus, type 1 diabetes mellitus with target organ lesion, and chronic kidney disease (GRF < 60 mL/min/1.73 m2).
High risk : Cardiovascular risk ≥5 and <10 % for fatal atherosclerotic events or one elevated risk factor (severe hypertension, familial dyslipidemia).
Moderate risk : Cardiovascular risk ≥1 and <5 % for fatal atherosclerotic events.
Low risk : Cardiovascular risk <1 % for fatal atherosclerotic events.
Management of Dyslipidemia
The correlation between blood levels of cholesterol and cardiovascular disease was established in the twentieth century, and in the 1950s the development of hypolipemiants was started . It took about 35 years for the first statin to be approved by FDA, and now there are semisynthetic (pravastatin and simvastatin) and synthetic statins (fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), with more than 30 million people currently taking statins [19, 20]. Statins are responsible for 25–35 % reduction on plasma levels of LDL-cholesterol and reduce the incidence of heart infarction on 25–30 % [16, 19].
Mechanism of Function: Pleiotropic Effect of Statins
Statins inhibits HMG-CoA reductase (hepatic enzyme responsible for cholesterol synthesis), increases cellular reabsorption of low density lipoprotein cholesterol (LDL) by inducing expression of LDL-receptor and thus, reducing blood levels of LDL-cholesterol, has poor effect increasing serum levels of HDL [20, 21].
It also diminishes the cardiovascular events by reducing endothelial lesion, improving production of nitric oxide and decreasing production of free radicals of oxygen. Statins have anti-inflammatory action and promote atherosclerotic plaque stability, reducing the progression of plaques and diminishing previous lesions [9, 22]. It reduces levels of high-sensitivity C reactive protein, reducing cardiovascular events even though blood cholesterol levels are normal [9, 20, 23, 24].
Most common side effects are myopathy and liver toxicity, in rare cases leading to kidney insufficiency due to rhabdomyolysis . Patients at increased risk for side effects are those at older age, with low body mass index, hypothyroidism, multisystem disease and alcohol abuse, previous renal and hepatic dysfunction, female gender, and in perioperative periods. There are few cases of autoimmune-induced myopathy caused by statins and slight higher rates of diabetes . The risk of side effects is very low especially when compared to impaired risk of cardiovascular event without statin in patients with moderate or high risk [15, 26–28].
The patients should be assessed individually, but in the absence of other risk factors the screening starts at 40 years for man and 50 years (or postmenopausal) for woman . Patients with risk factors, such as current smoking, diabetes, arterial hypertension, obesity (body mass index above 27, waist circumference ≥93 cm for men and ≥90 for women), familial history of premature coronary artery disease or familial hyperlipidemia, rheumatic or inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel diseases), chronic obstructive pulmonary disease, chronic HIV infection and antiretroviral therapy, chronic kidney disease, abdominal aneurysm, genetic dyslipidemias (xanthomas, xanthelasmas, FH), and erectile dysfunction must to be investigated for hyperlipidemia independent of age [16, 28, 29].
How to Screen?
Every patient should be evaluated by medical history , physical examination, and blood levels dosage of total cholesterol (TC), LDL, HDL, TG, glucose, and renal function (glomerular filtration rate, GFR). If dosage of LDL isn’t available and triglycerides <400 mg/dL, LDL can be calculated with Friedewald formula LDL = TC − HDL − TG/2.2 (mmol) and LDL = TC − HDL − TG/5 (mg/dL).
Calculating non-HDL cholesterol (total number of atherosclerosis particles) and Apoprotein B promotes better risk evaluation when compared to LDL only in patients with diabetes mellitus or metabolic syndrome. Non-HDL = VLDL + IDL + LDL (VLDL = TC/TG, if TG < 400).
Other markers such as Apoprotein B , Apoprotein A1 , and Lipoprotein(a) may be considered for risk evaluation. Apoprotein B is the most atherogenic of the lipoprotein and has a good correlation with LDL levels. It is considered a second-line marker in risk evaluation and a good predictor of cardiovascular risk . On the other hand, Apoprotein A1, as the major protein of HDL, is correlated with HDL blood levels. Lipoprotein(a) provides complementary information in families with premature cardiovascular disease [15, 16, 28, 29].
Who Should Take This Drug?
Statins are indicated for high blood levels of LDL-cholesterol and for patients with cardiovascular risk ≥7.5 % . For every reduction of 40 mg/dL in LDL-cholesterol, there is a corresponding 24 % reduction in major cardiovascular events [15, 17, 32, 33].
Statins should also be considered for patients with atherosclerosis [9, 31, 34], diabetes mellitus, asymptomatic patients with multiple risk factors (>5 % cardiovascular risk in 10 years), hypertriglyceridemia (TG > 500 mg/dL need statins combined to fibrates), and >21 years with elevated LDL . Low levels of HDL-cholesterol are independent and are an inverse predictor of cardiovascular disease, since for every 1 mg/dL increase in HDL, there is a lowering in 2–3 % for the risk of coronary artery disease .
Peripheral vascular surgery : Statins have a protective effect on cardiovascular causes of death, improving pain-free walking distance and controlling inflammatory state and progression of atherosclerosis [2, 6, 8, 9, 11, 31]. It also decreases rates of amputation, patency rates after procedures, and limb salvage . Although starting statins perioperatively increases the incidence of myopathy, risk is outweighed by benefits [15, 34].
Liver disease : Use of statins is safe in patients with altered liver enzymes (less than 3 times upper limit ) leading to the decrease of cardiovascular events in 68 %. The risk-to-benefit ratio was greater in patients with altered liver test, elevated dosage of ALT, and a high relation ALT-to-AST is a strong predictor of severe coronary disease. The benefits of statins in patients with altered liver enzymes above 3 times the upper limit remains unclear [15, 29, 37].
Targets of Treatment
There is no target LDL-cholesterol to achieve [6, 11, 12, 17]. The main objective of treatment is to decrease LDL level by 50 % or more. For every 1 mmol/L (40 mg/dL) reduction of LDL, cardiovascular morbidity decreases in 22 % [15, 27, 33].
Benefits are seen in reduction:
Regular blood tests, such as cholesterol and fractions , liver function, and non-HDL (includes also apolipoprotein B), should be evaluated to confirm response to treatment and adhesion to treatment [15, 16, 32].
Intensive statin regimens reduce 15 % more cardiovascular events than less intensive therapy and are indicated for patients with peripheral artery disease [8, 9, 38], with 13 % reduction of coronary death and nonfatal myocardial infarction, 19 % reduction of coronary revascularization, and 16 % reduction of ischemic stroke, but with elevation of hepatic enzymes [31, 39]. In more intensive regimens, for each 1 mmol/L (40 mg/dL) reduction in LDL, all-cause mortality and coronary artery disease were reduced in 10 % and 20 %, respectively [15, 17, 18, 27, 29, 40]. Intensive regimen is recommended for patients with >7.5 % CV risk and >75 years without contraindications .
Statin Therapy: Daily Doses
High intensive regimen : Atorvastatin 80 mg and rosuvastatin 20–40 mg .
Moderate intensive regimen : Atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–40 mg, pravastatin 40–80 mg, lovastatin 40 mg, fluvastatin 40 mg bid, fluvastatin XL 80 mg, pitavastatin 2–4 mg .
Low intensity regimen : Simvastatin 10 mg, pravastatin 10–20 mg, lovastatin 20 mg, fluvastatin 20–40 mg, pitavastatin 1 mg .
Hipolipedemiant Non-statin Drugs
Bile acid sequestrants (cholestyramine , colestipol , and colesevelam ): Such class of drugs binds to bile acid during digestion impeding their reabsorption and increasing clearance of hepatic cholesterol for production of new bile acid, therefore increases LDL-receptor activity and decreases serum rates of LDL-cholesterol [15, 33]. Doses of 24 g of cholestiramine, 20 g of colestipol, or 4.5 g of cholestagel decreases LDL-cholesterol in 18–25 % with no effect on HDL. Side effects are gastrointestinal (flatulence, constipation, dyspepsia, and nausea), reduced reabsorption of fat-soluble vitamins and important drug interaction (administration 4 h before or 1 h after other drugs) . When used in association with statins, there is an additional decrease of 10–20 % of LDL-cholesterol .
Cholesterol absorption inhibitors (ezetimibe) : Such class of drugs reduces absorption of cholesterol and bile acid without intervene in fat-soluble vitamins metabolism . As sole treatment, diminishes LDL-cholesterol levels in 15–22 % and combined to statins, lowers LDL-cholesterol in 30–44 %. Second-line treatment, normally prescribed with statins [15, 36]. Side effects are related to alteration of hepatic function and muscle pain. The recommended dose is ezetimibe 10 mg daily .
Nicotinic acid : In a daily dose of 2 g, such drugs increase HDL by 25 %, decrease LDL in 15–18 % and TG in 20–40 %, and reduce Lipoprotein(a) in more than 30 %. They are better indicated in familial hyperlipidemia and metabolic syndrome patients .
Fibrates : Such class of drugs is for the treatment of hypertriglyceridemia, generally when triglycerides are >2.3 mmol/L (or >200 mg/dL). It can reduce cardiovascular disease in 13 % . Side effects are related to gastrointestinal disturbance, myopathy, elevation in hepatic enzymes, skin rash , pancreatitis, and deep vein thrombosis (impaired metabolism of homocysteine) .
Platelets have a significant role in atherothrombosis : Rupture of an atherosclerotic plaque induces platelet aggregation and vasoconstriction resulting in acute arterial occlusion [1, 6, 13, 41]. Antiplatelet therapy prevents platelet aggregation and represents, beside statins, one of pillars of treatment of cardiovascular disease [1, 5, 7, 11, 13, 41–43]. In patients with moderate risk, antiplatelet therapy reduces 10–15 cardiovascular events per 1000 [9, 43]. In high risk patients, antiplatelet reduced in 23 % incidence of cardiovascular events (vascular death, nonfatal myocardial infarction, and nonfatal stroke) [9, 18, 42, 43]. Similar benefits are demonstrated when aspirin is initiated after stroke and transient ischemic attack . In patients with intermittent claudication , antiplatelet therapy lowers the rates of all-cause and cardiovascular death [7, 9, 44].
Aspirin has a commercial use as anti-inflammatory drug since beginning of 1900, but its antiplatelet action was reported only in 1953 and elucidated in 1971 . It causes irreversible inactivation of cyclooxygenase, inhibiting conversion of arachidonic acid into thromboxane A2 and prostaglandin I1 [1, 13, 22, 41–43, 45, 46].
The effect of aspirin is dose dependent and cumulative and endures all life span of platelets (8–10 days), with 75 mg of aspirin reaching antiplatelet effect [42, 43, 45]. Doses of 75–150 mg/daily shows similar effects when compared to moderate and high doses (160–1500 mg), but doses >325 mg/daily show an increased risk of bleeding and gastrointestinal side effects [3, 18, 42, 43, 47].
The use of doses of aspirin 75–325 mg/daily decreases in 12–14 % cardiovascular events (myocardial infarction, stroke, and cardiovascular death), diminishes in 21 % the risk of cardiovascular death, and prevents recurrent stroke in 1.5 % [6, 41–43, 45, 47]. The secondary prevention effect is well established in coronary artery disease, peripheral artery disease , and cerebrovascular disease [6, 8, 41]. there is no reduction in cardiovascular events in patients without established cerebrovascular or peripheral artery diseases and there is an increased risk of bleeding [6, 48].
Aspirin side effects relate to upper gastrointestinal symptoms and an increased risk of gastrointestinal bleeding (<1 %), vasoconstriction of renal circulation, and a nonsignificant increase in hemorrhagic stroke [41, 44, 45]. There are almost 20 % of aspirin resistance cases in population [1, 42, 46].
Thienopyridines (Clopidogrel, Ticlopidine, and Prasugrel)
Thienopyridines are selective and irreversible blockers of ADP-receptor which has its antiplatelet effect due blockade of glycoprotein IIb/IIIa complex [1, 6, 9, 22, 41, 42, 46, 49, 50]. It also has anti-inflammatory effects by reducing high-sensitivity C reactive protein, stabilizing atherosclerotic plaque, and diminishing intimal hyperplasia after endothelial lesion . Ticlopidine has shown better results in reducing stroke, myocardial infarction, and vascular death when compared to placebo .
Clopidogrel shows better results in preventing secondary coronary artery disease, peripheral artery disease, and recurrent stroke when compared to aspirin. Clopidogrel reduces in 8.7 % the risk of ischemic stroke and death from vascular causes and also decreases in 23.8 % the incidence of myocardial infarction, with no increased risk of bleeding [2, 3, 6, 8, 9, 11, 12, 18, 22, 31, 42, 43, 47, 49]. Incidence of resistance to clopidogrel is 16–25 % [1, 6, 42, 49, 50].
Prasugrel is an irreversible thienopyridine approved only for the treatment of acute coronary syndrome and patients undergoing percutaneous coronary intervention. It demonstrates reduction of 19 % in death, nonfatal MI or stroke when compared to clopidogrel [1, 41, 47]. Has elevated risk of fatal bleeding in patients >75 years and underweight (<60 Kg) . Side effects of thienopyridines are related to bone marrow depression (neutropenia), rash, and diarrhea [41, 44, 49]. Ticlopidine is taken at 250 mg twice a day and clopidogrel at 75 mg/daily with loading doses of 300 mg .
Other Antiplatelet Drugs
Thrombin protease-activated receptor (PAR-1) blockers (vorapaxar and atopaxar ): Decrease cardiovascular risk but at a cost of an increased risk of bleeding [2, 8]. When applied for peripheral artery disease , vorapaxar decreases the risk of acute limb ischemia and peripheral revascularization [1, 2, 8, 11]. Vorapaxar is taken at dose of 2.5 mg daily .
Glycoprotein IIb/IIIa receptor blockers (abciximab , tirofiban , and eptifibatide ): Have an antiplatelet effect due blocking fibrinogen binding site [1, 41, 46]. Their use is intravenous and restricted to acute coronary syndrome and patients undergoing percutaneous coronary intervention . Studies suggest perioperative benefits of abciximab in patients with critical limb ischemia or poor distal out-flow . Side effects are related to thrombocytopenia .
Ticagrelor : Reversible antagonist of P2Y12-receptor (binds in a different site on ADP-receptor of clopidogrel) that demonstrates superiority on prevention of cardiovascular death, myocardial infarction, and stroke when compared to clopidogrel, however with higher rates of intracranial bleeding [1, 6, 11, 41, 47]. Their side effects are bradyarrythmias, dyspnea, and impairment of renal function . Is indicated only in dual therapy with aspirin for the treatment of acute coronary syndrome and for patients undergoing percutaneous coronary intervention [6, 41, 47].
Truflusal : Is a new COX-1 inhibitor under investigation, preliminary studies demonstrate similar efficacy to aspirin in preventing recurrent vascular events with less intracerebral bleeding . Not FDA approved.
Sarpogrelate : Decreases platelet levels of 5-hydroxy-tryptamine (5-HT); it’s been studied in peripheral artery disease with similar results to aspirin with less bleeding .
Dual Platelet Drugs
Residual risk of cardiovascular events is high in the use of aspirin alone, and adding another antiplatelet drug increases antiplatelet effect [6, 42, 43]. Combination of aspirin and other antiplatelet (clopidogrel, ticlopidine, ticagrelor) has shown 20–36 % additional decreasing in cardiovascular risk in patients and is indicated in the management of acute coronary syndrome and patients undergoing percutaneous coronary or peripheral intervention, with slightly higher rates of bleeding [8, 31, 41–43, 51, 52]. In patients with previous stroke or peripheral artery disease , dual antiplatelet therapy didn’t show benefits in preventing new events and had an increased risk of major bleeding and death [2, 3, 9, 12, 18, 31, 42, 47, 51, 53].