The goals of epilepsy therapy are to achieve seizure freedom while minimizing adverse effects of treatment. However, producing seizure-freedom is often overemphasized, at the expense of inducing adverse effects of treatment. All antiepileptic drugs (AEDs) have the potential to cause dose-related, “neurotoxic” adverse effects . Such adverse effects are common, especially when initiating AED therapy and with polytherapy. Dose-related adverse effects may be obviated in most patients by dose reduction of monotherapy, reduction or elimination of polytherapy, or substituting for a better tolerated AED. Additionally, all older and several newer AEDs have idiosyncratic adverse effects which usually require withdrawal in an affected patient, including serious rash , hematologic dyscrasias, hepatotoxicity, teratogenesis in women of child bearing potential, bone density loss, neuropathy, and severe gingival hyperplasia. Unfortunately, occurrence of idiosyncratic AED adverse effects cannot be predicted or, in most cases, prevented in susceptible patients. This article reviews a practical approach for the definition and identification of adverse effects of epilepsy therapies, and reviews the literature demonstrating that adverse effects result in detrimental quality of life in epilepsy patients. Strategies for minimizing AED adverse effects by reduction or elimination of AED polytherapy, appropriately employing drugsparing therapies, and optimally administering AEDs are outlined, including tenets of AED selection, titration, therapeutic AED laboratory monitoring, and avoidance of chronic idiosyncratic adverse effects. Although analysis of quality of life (QOL) in epilepsy began later than many other medical fields, an ever growing body of epilepsy QOL research has accumulated over the last decade. A review of all the validated instruments for research and clinical use in epilepsy is beyond the scope of this article; two excellent recent reviews addressing the range of available tools and their relative advantages and potential uses are available for the interested reader ,28. In gEpilepsy QOL research has re-emphasized the importance of producing seizure-freedom as a principle goal for all patients, but has also revealed that the interictal state is a principle determinant of a patient’s own perceived quality of life; in addition to seizures themselves, a patient’s daily functioning, cognitive status, mood states, social functioning, and the closely related factor of perceived adverse treatment effects determine how a patient feels about their overall QOL. QOL research in epilepsy has reshaped priorities in epilepsy care, calling for clinicians to maintain vigilance over the patient’s interictal status in the monitoring of mood, cognition, social functioning, and adverse effects in addition to seizure burden.1.An adverse effect of therapy may be defined as any clinical symptom, sign, or laboratory dyscrasia which is deemed undesirable to the patient, the physician, or both. Adverse effects, while always unintended, are not entirely unexpected in epilepsy care; adverse effects are unfortunately common, reported in 40-50% of epilepsy patients receiving monotherapy AED treatment ,21. MostIdentifying AED toxicity in affected patients is problematic for several reasons. Some patients may have grown used to feeling ill while receiving AED therapy and complacently accept adverse effects as a natural consequence of their treatment. Additionally, patients are often understandably reluctant to “make waves” during clinic visits. Patients’ fears of ongoing seizures tend to overshadow complaints about medication toxicity, and conversely, seizure-free patients are often too comfortable with and grateful for their outcomes to broach the risk of lowering or withdrawing AEDs producing adverse effects, despite limitations in QOL.Furthermore, patient reticence to raise concerns over toxicity is compounded by physicians’ preoccupation with assessment of seizure events (perhaps driven in part by overly busy clinics which discourage thorough communication), leading physicians to focus only on seizure histories while neglecting to inquire about AED toxicity and other important related interictal factors. Physicians also typically place greater concern about serious idiosyncratic adverse effects despite their infrequency due to fear of litigation; instead of being vigilant to bedside measures of common adverse effects, physicians may instead too often focus on clinical laboratory values such as AED blood levels, chemistries, liver function testing, and complete blood counts. However, while a valuable adjunct to guide clinical decision-making, AED blood levels are neither a fail-safe for detecting clinical toxicity or ensuring therapeutic seizure-freedom, and uncertainty exists as to the interpretation and clinical value of blood levels for many of the newer AEDs.2) ..2) [3].2) questionnaire [Antiepileptic drug adverse effects are a principle determinant of QOL in epilepsy patients. Proactive, quantitative assessment of adverse effects enables their identification and appropriate alteration of AEDs to reduce adverse effects. A recent randomized controlled trial of a rapid diagnostic tool for identification and quantification of AED adverse effects in a clinical office setting has been conducted, which evaluated the self-completed Adverse Event Profile  is desirable. Many medically refractory epilepsy patients require chronic polytherapy, and the recent AAN/AES Practice Guidelines for the treatment of refractory epilepsy stated that all newer FDA-approved AEDs have Class 1 evidence for adjunctive treatment of refractory partial-onset seizures in adults, and there is ample evidence to conclude that lamotrigine, oxcarbazepine, and topiramate are effective for the treatment of refractory partial seizures in children . While nEleven new antiepileptic drugs rather than nine. When polytherapy is prescribed, great care must be taken to avoid excessive drug dosing and drug-drug interactions that may increase clinical toxicity through pharmacokinetic factors. Considerable research has demonstrated that the most deleterious result of polytherapy is an increased risk for development of adverse effects, including pharmacodynamic dose-related neurotoxic effects, severe life threatening rash with combined lamotrigine and valproate, and teratogenic effects in children born to pregnant women receiving AED polytherapy. A recent survey of patients with epilepsy demonstrated that central nervous system-related adverse effects, especially memory complaints and fatigue, appear to be most frequent overall, and that polytherapy was more frequently associated with these adverse effects than monotherapy .Unfortunately, only a small number of refractory patients can be rendered seizure-free with AED polytherapy, although some patients benefit substantially by reduction of seizure burden. A recent pivotal prospective observational study demonstrated that only 3% of patients who fail two sequential initial monotherapies are subsequently rendered seizure-free by polytherapy . Since AFailure to produce seizure control after even one well-tolerated, optimally administered monotherapy AED is an ominous prognostic feature that may portend medical intractability in many patients . After fThe superiority of epilepsy surgery over medical therapy for well-localized mesial temporal lobe epilepsy, the most common refractory partial epilepsy syndrome, has been well established in a randomized controlled trial . PatientThe vagus nerve stimulator (VNS) is a FDA approved device as an adjunctive treatment for refractory partial-onset onset seizures. Long-Term follow-up outcome data suggests that over 40% of patients experience a 50% or greater reduction in their seizures . More reSpecialized diets may be a useful adjunctive treatment for epilepsy. The best studied of these is the ketogenic diet. The ketogenic diet is a high fat, low protein, low carbohydrate diet that induces systemic ketosis, which has an antiepileptogenic effect on the brain. The ketogenic diet is most often successfully employed in children, but may also be tried in adolescents and adults. Unfortunately, unless rigid compliance is assured, the ketogenic diet produces little benefit and, in general, most adolescents and adults have limited tolerance of the diet. However, highly motivated and desperately refractory epilepsy patients may benefit from the ketogenic diet. An alternative that is often more tolerable, but not yet robustly studied, is the modified Atkins diet, a high fat, moderate protein, low carbohydrate diet that induces mild ketosis. The risk of inducing undesirable lipid abnormalities, metabolic states, and other long-term health effects of these dietary therapies also remain unclear.Identifying and treating seizure aggravators is also an important consideration. Recent studies have suggested that obstructive sleep apnea (OSA) is a frequent co-morbidity in refractory epilepsy, and a pilot treatment trial of nasal continuous positive airway pressure (nCPAP) in patients with refractory epilepsy and co-morbid OSA showed substantial seizure reduction without alteration of AED therapy -19. PrimGuidelines for choosing and optimally administering epilepsy therapies are currently lacking. Until evidence-based guidelines are developed, optimal selection and administration of epilepsy therapies must be highly individualized by synthesizing available data and patient qualities and preferences. AED selection, titration, target dosage, basic pharmacokinetic properties, potential AED and non-AED drug interactions, therapeutic AED laboratory monitoring, and avoidance of chronic idiosyncratic adverse effects are all considerations when attempting to minimize adverse effects of AED administration. There are currently no clear evidence based algorithms to guide these important factors in AED treatment. Nonetheless, common treatment principles underlie the choosing, dosing, sequencing, and monitoring of AED therapy in epilepsy care. While a comprehensive guide to employing AED therapy is beyond the scope of this article, several basic principles for optimal AED administration include:Choose AED therapy appropriate for the epilepsy syndrome;Consider patient characteristics and co-morbidities when choosing AEDs;Employ AED monotherapy at the lowest effective dosage to achieve seizure freedom;Reserve AED polytherapy (combining two or more AEDs) for refractory patients and minimize total drug load to limit adverse effects;Treat according to the patient’s clinical response, not the AED level;Monitor for long-term complications of older AED therapy and consider withdrawal of therapy when appropriate; andChoose affordable AED therapy.A few of these points which are particularly important for avoiding and minimizing adverse effects are next considered.1. When choosing and utilizing AEDs, a considerable amount of pharmacological knowledge and clinical wisdom is necessary for successful patient outcomes. Patient’s characteristics such as age, sex, co-morbidities, and co-existing medications are important determinants of proper drug selection and use. These factors most frequently guide which AED may have the most desirable pharmacokinetic and phamacodynamic properties to avoid the development of undesirable adverse effects, and examples of patient characteristics that impact on AED selection are now discussed.A first general principle in AED choice and usage is to employ AED monotherapy whenever possible, since monotherapy is just as effective, or more effective, than polytherapy. Monotherapy limits the potential for adverse effects and drug interactions. Specific AEDs are itemized with accompanying information on clinical spectrum of uses, pharmacokinetics, typical dosing and blood levels, and cardinal adverse effects in Table Older patient age is a factor suggesting a heightened vulnerability to the development of dose-related neurotoxic adverse effects. Several recent studies have shown that newer AEDs are better tolerated in the elderly , 32. FemAED dosing must be individualized to achieve optimal results. The usual strategy is to titrate the AED toward a target dose that has proven effective for most individuals in pivotal clinical studies and in subsequent clinical experience. Dose adjustment can then be made in the event of adverse drug reactions or recurrent seizures. If the endpoint of seizure freedom is preserved, maintaining a lower but clinically therapeutic AED dosage and level (if obtained) is entirely acceptable. If a patient continues to experience breakthrough seizures, raising the AED dose to the maximal dose tolerated is sometimes necessary, although recent evidence demonstrates that only a minority of patients become seizure-free when dosed above the usual population range, so a practical viewpoint of treatment futility should be realized when patients experience frequent breakthrough seizures despite adequate AED dosages . TherapeOverlapping AEDs in transitional polytherapy  is the preferred method when introducing a new AED monotherapy. Abruptly stopping the existing AED increases the risk of seizures while introducing the new adjunctive AED too rapidly may induce adverse effects that taint the patient’s perception of what could otherwise be an effective therapy. Recently, an expert consensus panel was convened to address the issue of how best to convert between AED monotherapies when initial monotherapy fails due to lack of efficacy or tolerability, utilizing the Delphi model of determining consensus on strategies for best practice . The expMost patients should receive two sequential AED monotherapies with differing mechanisms of action prior to attempting chronic polytherapy. In general, a similar strategy to that agreed upon by the expert panel for monotherapy conversions should also be used when initiating addition of a second (or third) adjunctive AED for use as chronic polytherapy. A recent trial well illustrated the potential for increased toxicity with adjunctive AED therapy . This raWhen utilizing polytherapy, the clinician must be knowledgeable about the potential for pharmacokinetic and pharmacodynamic AED interactions, which influence the risk of developing adverse effects. While an exhaustive review of drug interactions is beyond the scope of this article, a few illustrative scenarios will suffice to make this important point. In general, the main pharmacokinetic interactions to consider in AED polytherapy are potential Cytochrome P450 metabolism competition, and protein binding and displacement. Co-administration of the enzyme-inducing AEDs  with inducible AEDs  increases and hastens the metabolism of the inducible AED. In complex polytherapy regimens, reducing the dose of enzyme-inducing AEDs  will “de-induce” the regimen, thereby increasing the serum concentrations of highly inducible AEDs (such as lamotrigine and topiramate), leading to optimized pharmacokinetics of the inducible AED and improved seizure control in some instances . ConversPharmacodynamic adverse effects are especially difficult to avoid when using polytherapy, as dose-related neurotoxic and cognitive adverse effects are more prevalent in polytherapy. Cognitive impairments commonly accompany polytherapy and are often subtle and difficult to identify without specifically questioning the patient. While standard office assessment of cognition often shows minimal impact, detailed neuropsychological and electrophysiological measures often show impairments in attention, concentration, executive function, and memory in patients receiving AED therapy ,29,34,35An intimately related issue to clinical toxicity meriting discussion is “laboratory” toxicity, that is, when AED blood levels fall above established “normal” therapeutic ranges. Philosophies on the use of AED blood level monitoring differ, but most agree that blood levels should be considered only a guideline to treatment in most cases. AED levels should not be perceived as an absolute indication for altering AED dosing, divorced from clinical judgment of the patient’s seizure control or adverse effects. Blood level monitoring can help guide therapy, but so-called “therapeutic” levels are derived from treatment of populations. An individual patient may require a lower or higher intensity of AED therapy to achieve optimal results. In general, AED levels are most useful when testing a clinical hypothesis. “Routine” or scheduled levels should be generally discouraged, an exception being chronic phenytoin therapy in institutionalized patients (where “zero-order” kinetics from non-linear hepatic metabolism may lead to drug accumulation and toxicity). AED blood level monitoring is further reviewed in the next article in this series.Unfortunately, accurate prediction of the development of idiosyncratic toxicities of AEDs is not currently possible. The highest risk of idiosyncratic reactions associated with most older AEDs such as serious rash, hepatotoxicity and hematologic dyscrasias is during the first 6-12 months of therapy, and extremely rare thereafter, so that routine monitoring for these problems is rarely necessary in otherwise healthy patients. Intermittent blood testing for monitoring of liver function tests and hematologic functions is reasonable, although not of proven value; consider obtaining baseline AST/SGOT and complete blood count (CBC) with repeated measures at 1, 3, and 6 months following initiation of therapy with older AEDs, and measure baseline serum sodium before initiation of carbamazepine and oxcarbazepine (which may result in hyponatremia) with repeat testing after two months, perhaps with earlier or more frequent testing in elderly patients or those receiving sodium-wasting diurectics. If felbamate is used, baseline and weekly liver function and CBC testing is indicated per package insert labeling. Most experts continue such extensive monitoring until at least several months of clinical and laboratory stability have been reached, given the potential for fatal aplastic anemia and hepatotoxicity, and then continue periodic monitoring thereafter.There is mounting concern that patients on chronic therapy with older AEDs are at risk for bone density loss and fractures. Enzyme-inducing AEDs  have the potential to decrease bone density through secondary hypoparathyroidism and decreased Vitamin D levels, and some evidence suggests that non-inducers such as valproate also lead to decreased bone density . Many epWomen of child bearing potential (WCBP) are at risk for two worrisome AED-related adverse effects: pregnancy due to oral contraceptive failure, and AED-induced fetal teratogenesis. Avoiding EIAEDs in WCBP whenever possible is prudent to avoid hormonal contraceptive failure, and counseling WCBP about the hazard of contraceptive failure with EIAEDs is important. WCBP should be instructed to utilize double-barrier contraception in addition to their hormonal methods when receiving EIAEDs. Prior to a planned pregnancy, weaning the WCBP from AEDs when she is seizure-free and at low risk of seizure recurrence, or utilizing monotherapy when AED therapy is necessary whenever feasible, is especially important in WCBP since polytherapy use has been linked to teratogenesis. While there is not yet unequivocal evidence regarding AED safety or hazards during first trimester exposure in pregnancy, available evidence suggests that phenobarbital and valproate should be avoided when possible . Although no certain evidence basis exists. most agree that WCBP taking AEDs should receive folic acid 1 milligram daily , especially those on EIAEDs. Some experts recommend high dose folic acid for women receiving valproate, up to 4 milligrams daily.Chronic phenytoin exposure is of particular concern, given its relatively common association with cosmetic adverse effects including gingival hyperplasia (which may be severe enough to warrant repeated gingivectomies), and the rare but real potential of axonal peripheral neuropathy and irreversible cerebellar ataxia. Many experts now feel that because of these risks, phenytoin use should be for a relatively short term , after which time the patient can be offered the opportunity to transition to another AED if continued therapy is necessary.One additional idiosyncratic toxicity meriting mention here is risk of serious rash with lamotrigine, which appears to be related to several factors, at least one of which is modifiable: pediatric age, concurrent valproic acid therapy, and overly rapid initial titration of lamotrigine. When initiating lamotrigine, paying strict attention to AED co-medications and adhering strictly to the recommended package insert titration instructions is required.Epilepsy QOL research suggests that too little clinician attention has been focused upon the interictal state. One critical determinant of QOL in epilepsy patients is whether they suffer from adverse effects of AED therapy. Research has shown that identification of AED adverse effects is aided by using the Adverse Events Profile (AEP), a validated clinical tool easily completed by patients in the office setting within a few minutes, and that considering this information leads to appropriate alterations in AED therapy that may improve patient QOL. Strategies for reducing common dose-related “neurotoxic” adverse effects include optimal AED selection, titration, co-therapy reduction, utilizing monotherapy, and elimination of polytherapy when feasible. In refractory epilepsy, utilizing drug-sparing therapies such as epilepsy surgery, VNS or dietary therapies, or diagnosis and treatment of co-morbid primary sleep disorders may minimize AED doses and drug load, thereby minimizing adverse effects. Idiosyncratic adverse effects cannot be reliably predicted with current clinical tools and strategies for prevention of specific idiosyncratic adverse effects such as teratogenicity and bone loss are unfortunately lacking, but treating women of child bearing potential receiving AED therapy with folic acid and daily supplemental calcium is reasonable . Vigilance toward the current presence and future possible evolution of adverse effects of epilepsy therapy should be considered a chief responsibility of epilepsy clinicians, since proactive AED alteration may effect improvements in patient QOL.


Role of antiplatelet therapy in secondary stroke prevention is of major significance. Antiplatelet agents predominantly in use are aspirin, clopidogrel, and combination regimes. The review focuses on the optimization of antiplatelet regimen based on evidence obtained from randomized-controlled trials, on different antiplatelet regimes and the risk assessment that may be unique to each patient. Stroke is the second most common cause of death and disability today. The WorlShould aspirin still be the most valued antiplatelet agent?What is the optimal aspirin dosage?Are combination antiplatelet agents with different modes of action better than a single agent?Are the new antiplatlelet drugs like clopidogrel superior to aspirin?Are more potent antiplatelet drugs e. g., GP IIbIIIa antagonists more effective/? safer than aspirin monotherapy?The majority of research in secondary stroke prevention supports the clinical value of aspirin. Aspirin has been most time-tested. Other regimes have been discovered, but aspirin remains the most non-controversial, inexpensive and reasonably effective , albeit with a fraction lesser efficacy. The questions that remain unanswered satisfactorily are:The Antiplatelet Trialists Collaboration (ATC) publisheInhibition of a measurable property of platelets such as adhesion, retention, or aggregation;Inhibition of platelet-induced thrombus formation;Prolongation of survival of radioactively labeled platelets in clinical or experimental situations in which platelet survival may be decreased.To be considered as an antiplatelet agent, the following characteristics apply:Each of these antiplatelet agents have a unique mechanism of action.Aspirin is a cyclooxygenase inhibitor, whereas the thienopyridines, ticlopidine, and clopidogrel inhibit the binding of adenosine diphosphate to its platelet receptor. Dipyridamole is considered to be a weak antiplatelet agent, but it is thought to enhance the antithrombotic activity of the vessel .Aspirin, the most commonly used antiplatelet agent, has been available for a long time. Aspirin remains an inexpensive, relatively safe, effective, easy-to-use, and widely accessible therapy in our armamentarium for stroke and cardiovascular disease prevention.–9 In theAspirin remains the most widely studied drug and at doses of 75 to 150 mg and is atleast as effective as a higher daily doses in reducing stroke risk. In comparison with placebo, the relative risk reduction for stroke, MI, or vascular death, is 13%. Table Higher doses have been tested in other trials and not found to confer any greater risk reduction. The optimal dosage of aspirin therefore continues to be elusive and at best the consensus seems to be 150–300 mg/day in most clinical situations.Aspirin has a well-known safety profile. Gastrotoxicity such as in-digestion, nausea, heartburn, vomiting, and gastro-intestinal bleeding are well-defined side effects. One of tTiclopidine became a popular agent for the prevention of recurrent stroke in the early and mid 1990s,–11 but vPost hoc analysis of the TASS data suggested that non-whites had about 10% fewer adverse events and a greater risk reduction for key vascular outcome events.[Two large scale randomized trials, CATS and TASSe events. These daThe main adverse events associated with ticlopidine are diarrhea, other GI symptoms, rash, neutropenia, and thrombocytopenia. Hence, it is mandatory to obtain blood counts every 2 weeks in the first 3 months of therapy. TTP although rare can be fatal. It is estimated to occur one per 2000 to 4000 users.–11post hoc analyses of CAPRIE trial, the benefit of clopidogrel was demonstrated to be amplified among high-risk subgroups, including patients with a history of previous MI, stroke, and those receiving lipid-lowering therapy, patients with DM, prior cardiac surgery, clopidogrel produced a relative risk reduction of 14.9% versus aspirin for the primary CAPRIE end point.[Clopidogrel is a thienopyridine derivative chemically related to ticlopidine, which is superior to aspirin in stroke prevention.–13 The cTaken together the absolute difference between clopidogrel and aspirin is very small. Hence, a general use of clopidogrel in stroke patients is probably not justified. Clopidogrel is the agent of choice in patients with contraindications to or adverse effects on aspirin or in cases of aspirin failure. Also, clopidogrel seems to have an edge over aspirin in terms of effectively presenting stroke in subgroups of patients with coronary events; those with peripheral vascular disease, in women and in patients stented for carotid artery disease.The main side effects of clopidogrel alone are rash and diarrhea. Neutropenia has not been a concern. TTP may infrequently occur, a causal relationship seems uncertain.The MATCH (Management of Atherothrombosis with Clopidogrel in High-Risk patients with recent TIA or ischemic stroke) trial was a randomized double-blind placebo-controlled trial that compared aspirin (875 mg/day) versus placebo added on to patients receiving clopidogrel (75 mg) in 7599 high-risk patients with recent ischemic stroke or TIA and with atleast one additional risk factor. The duraThe European Stroke Prevention Study (ESPS) 2 was a randomized double-blind placebo controlled trial that compared aspirin alone (50 mg) daily, extended release dipyridamole alone (200 mg twice a day) to combined aspirin and ER dipyridamole and placebo in patients who had suffered either a TIA or stroke. End poinThe largest ever recurrent stroke prevention trial, PRoFESS, results were presented at European Stroke Congress in Nice last year. PRoFESS is a double blind placebo-controlled clinical trial performed at 695 sites in 35 countries, with more than 20000 patients randomized to receive extended-release dipyridamole (200 mg) plus ASA (25 mg) given twice a day or clopidogrel  dipyridamole did not meet prespecified criteria for noninferiority versus clopidogrel, but rates of recurrent stroke, the primary outcome, were similar between the groups.Therefore, the study did not show that aspirin plus extended-release dipyridamole or clopidogrel is superior to the other in the prevention of stroke. The findings provide additional safety and efficacy data physicians need in making individual treatment decisions for prevention of recurrent stroke or the combined end point of stroke, myocardial infarction, or death from vascular causes in their patients with stroke.On the basis of these results, although aspirin remains the most commonly prescribed antiplatelet agent in patients with stroke and cautious guideline committees have not strongly favored one of the newer agents over the other, low-dose aspirin plus extended-release dipyridamole became the preferred agent for clinicians determined to select the best of all possible evidence-based antiplatelet regimens for secondary stroke prevention. Indirect comparison of these trials logically suggested that the combination would be superior to individual agents. However, the results of the MATCH, CHARISMAIn an era of comparative effectiveness, when multiple agents are compared, randomized trials often cannot be understood in isolation, but must be interpreted in the context of sometimes complex networks of similar or relevant evidence. However, the reduction of such networks to clinical recommendations is not always straightforward. This concept gains much more significance when risk stratification and risk assessment in an individual patient is considered to impact the effectiveness of a given antiplatelet regimen.Current guidelines in Europe and the United States recommend that for antiplatelet therapy after a stroke, aspirin, aspirin plus dipyridamole, and clopidogrel are options for prevention of stroke recurrence, but there is no recommendation for the use of one of these agents over the others.In the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial, patients with vascular disease were randomized to lotrafiban 30 mg or 50 mg twice a day or placebo in addition to aspirin at a dose ranging from 75 mg to 325 mg per day. Follow-uP = 0.185).[P = 0.034).[Results of a randomized pilot trial, Cilostazol vs. Aspirin for Secondary Ischemic Stroke Prevention (CASISP), suggest that cilostazol is as effective as aspirin in preventing recurrent stroke, with significantly lower rates of bleeding. Cilostaz= 0.185). At the e= 0.034).Anticoagulation therapy is superior to antiplatelet therapy in preventing stroke in AF. CombininAtrial fibrillation (AF) affects 5% of people older than 65 years.Among patients with AF, the risk of stroke averages about 5% per year.The risk of stroke increases cumulatively with increasing age, previous transient ischemic attack or stroke, hypertension, diabetes, impaired left ventricular function, and a large left atrium.Management aims to identify and treat the underlying cause, control the ventricular rate, restore and maintain sinus rhythm, and minimize the risk of stroke.Warfarin reduces the risk of stroke by about two-thirds, and aspirin by about one-fifth.The risk of anticoagulant-associated hemorrhage increases with serious concomitant disease, and with poorly controlled hypertension and poorly controlled anticoagulation.All patients with chronic AF should be considered for oral anticoagulant therapy, and the decision based on the balance between the risks of thromboembolism and bleeding.The recommended international normalized ratio (INR) is 2.0-3.0.The consensus statements regarding AF and stroke prevention are:Treating 1000 “average” AF patients  with warfarin prevents about 30 strokes and causes at least two episodes of major hemorrhage each year. Treating 1000 AF patients with aspirin prevents about 15 strokes each year.in vivo surrogate marker, detected by transcranial Doppler ultrasound (TCD), may be useful as markers of risk in patients with carotid stenosis. During a single hour 's recording from the ipsilateral middle cerebral artery, asymptomatic embolization has been reported in ≈40% of patients with symptomatic carotid stenosis.[31Recent studies suggest that the risk of very early recurrent stroke is particularly high in patients with carotid artery stenosis, suggestistenosis.–29 MES astenosis.30 plaquestenosis.3132 tighenosis.31 and sympenosis.31 trial deenosis.31 emphasizIn younger stroke patients, cervical artery dissection (CAD) is considered among the most important stroke etiologies. The recuThe pathophysiology, clinical observations, and the systematic metaanalysis provide several putative arguments in favor as well as against immediate anticoagulation in CAD patients. Until evidence-based data are available, the Table Adjusted-dose UFH throughout pregnancy such as a subcutaneous dose every 12 h with APTT monitoringAdjusted-dose LMWH with factor Xa monitoring throughout pregnancyUFH or LMWH until Week 13, followed by warfarin until the middle of the third trimester, when UFH or LMWH is then reinstituted until delivery.For pregnant women with an ischemic stroke or TIA and high-risk thromboembolic conditions such as known coagulopathy or mechanical heart valves, the following options may be considered:AdjustedPregnant women with lower-risk conditions may be considered for treatment with UFH or LMWH in the first trimester, followed by low-dose aspirin for the remainder of the pregnancy. This has Class IIb, Level C evidence.It is common that patients who are scheduled for surgery are treated with antiplatelet agents due to their wide indications. The management of these antiplatelet agents in the perioperative period has a dual perspective: the risk of bleeding when the patient is operated under the effect of the antiplatelet agents against the risk of thrombosis if it has been withdrawn. The main challenges for the anaesthesiologist and the surgeon include patients with a coronary stent , those undergoing urgent surgery and those undergoing high bleeding risk surgery.Current recommendations include the maintenance of aspirin if possible throughout the perioperative period, in order to limit the risks of cardiological, vascular or neurological postoperative events, although this makes it necessary to assume a small risk for hemorrhagic complications in some patients. NevertheThere are no recommended guidelines as to whether and when to start secondary stroke prophylaxis after hypertensive intracranial hemorrhage. Although the risk factors remain identical and the risk of recurrence of strokes which may be ischemic exists in these patients, the risk of recurrence of hemorrhage versus infarct in these patients; risk of hemorrhage due to antiplatelet agents remain nebulous at best. Most strokologists verbally promulgate use of antiplatelet agents on an average 6 months after the intracranial hemorrhage.Aspirin is cheap, widely available, easy to administer, and relatively safe and effective. Although aspirin plus extended release dipyridamole, clopidogrel, and ticlopidine may provide added recurrent stroke prevention benefit over aspirin alone, the former drugs are far more expensive than aspirin and will vary in cost by region. Cost-effectiveness analyses, with their inherent limitations suggest that in high-risk subjects, aspirin plus extended release dipyridamole over aspirin, and clopidogrel over aspirin alone are recommended. However, debate continues to rage about whether aspirin or one of the other antiplatelet agents should be used as initial therapy for recurrent stroke prevention.in vivo thromboxane generation, 11-dehydrothromboxane B2.Concepts of antiplatelet resistance and failure are evolving. For aspirin, resistance may be defined as persistence of platelet activation and adhesion (as determined by platelet function studies) despite the administration of the drug, and failure as the occurrence of recurrent stroke or TIA despite administration of aspirin. Failure post hoc analysis was conducted using data from the ESPS-2 study. The rates of annual strokes and vascular events were determined for the aspirin + ER-DP group and the aspirin only group and were stratified by risk subgroup and univariate risk factors.[If we now assume that any drug or drug combination more effectively inhibiting platelet function is not more effective than aspirin monotherapy, is there a subgroup of patients who could still benefit from clopidogrel or benefit in a particular way from the aspirin + ER-DP, or aspirin+ clopidogrel combination? A  factors. The maxiTrial results are mere guidelines. They cannot be extrapolated indiscriminately to every patient encountered in clinical practice. These drugs are sometimes given indiscriminately to all patients who might remotely respond irrespective of the original guidelines. The indiscriminate use may dilute any potential therapeutic effects and exposes patients to possible adverse side effects.Although complex biochemical tests to document aspirin resistance or failure may not be justified in all patients, these two parameters which may impact the outcome of prophylaxis must be considerd and whenever deemed necessary must be carried out.Cerebral micorbleeds demonstrated by gradient echo technology on MRI scanning in patients taking aspirin may also play a predictive role in subsequent cerebral hemorrhage. To reduce drug-related cerebral hemorrhage, screening for cerebral microbleeds might be helpful before long-term antiplatelet therapy is started, and aspirin should be selected cautiously, particularly in patients with microbleeds at many sites.Unlike MI, stroke is a variegated entity, and the pathogenesis and therapeutic potential in cardiogenic and lacunar strokes are entirely different from those of cerebeal vasculitis. These completely diverse cerebrovascular pathogeneses behave differently and should be treated separately. The varied etiopathogenesis causing strokes may explain the differential response to antiplatelet regimes in individual patient.The question of how serious is the influence of pharmaceutical companies in our prescription practices is extremely poignant and of enormous ethical relevance. This needs intense soul searching. No doubt, industry and clinical practice can and be encouraged to live amicably and be symbiotic. But the ethics and science behind each prescription cannot be compromised. Since there is no wonder drug available till date.From time to time industry has tried to influence clinicians in their favor one way or the other with a proliferation of inducements. This trend has certainly wormed its way into the clinical practices and has raised alarm in institutes concerned with ethical medical practices. Hopefully, this trend will soon disappear.2Y12 ADP receptor antagonists , thromboxane receptor antagonists , and thrombin receptor (PAR-1) antagonists .[Emerging antiplatelet therapies presently being evaluated for secondary prevention of atherothromboembolism include other PWald and Law evaluated published meta-analysis to devise a single composite pill a polupill that would simultaneously reduce four major cardiovascular risk factors: raised LDL, high blood pressure, platelet aggregability, and raised blood homocyteine levels. The pillIt is of major importance to identify subgroups of patients with a very high risk of recurrence. In this subgroup of patients, clopidogrel as well as the combination therapies may be more superior to aspirin monotherapy.


Phlebovirus that causes periodic outbreaks of animal and human disease in Africa and the Arabian Peninsula. On the basis of its many competent vectors, its potential for aerosol transmission, and its progressive spread from East Africa to neighboring regions between 1950 and 2000, RVFV is ranked as a high-priority, emerging health threat for humans, livestock, and wildlife in all parts of the world.Rift Valley fever virus (RVFV) is a mosquito-borne Aedes species. Most often, local virus propagation is reactivated as these mosquitoes emerge from temporary ponds (dambos) formed by heavy rainfall in enzootic/endemic areas.Culex. Because livestock miscarriage and mortality rates are high, humans can also become occupationally exposed to RVFV by handling infected animal tissues or by aerosolization of body fluids.Rift Valley fever virus is typically maintained by vertical transmission among floodwater


Evaluation of patients who present to the hospital with acute undifferentiated chest pain or other symptoms and signs suggestive of Acute Coronary Syndrome (ACS) is often a clinical challenge.The initial assessment, requiring a focused history , a physical examination, an electrocardiogram (EKG) and serum cardiac marker determination, is time-consuming and troublesome. Recent investigations have indicated that increases in biomarkers of necrosis, inflammation, ischemia and myocardial stretch may provide earlier assessment of overall patient risk, help in identifying the adequate diagnostic and therapeutic management for each patient and allow for prevention of substantial numbers of new events.The purpose of this review is to provide an overview of the characteristics of several biomarkers that may have potential clinical utility to identify ACS patients. Patho-physiology, analytical and clinical characteristics have been evaluated for each marker, underlying the properties for potential routine clinical use.The biomarkers discussed in this review are promising and might lead to improved diagnosis and risk stratification of patients with ACS, however their clinical application requires further studies. It is important to define their clinical role as diagnostic markers, their predictive value and the specificity, standardization and detection limits of the assays. The term “acute coronary syndrome” (ACS) encompasses a range of thrombotic coronary artery diseases, including unstable angina (UA) and both ST-segment elevation (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI).Current estimates are that 1.7 million patients with ACS are admitted each year to hospitals in the United States .It is evident that the epidemiological importance of the phenomenon, the potentially lethal consequences for the patient, and the economical and legal implications for clinicians make the need of an adequate strategy of diagnostic and therapeutic management, including risk stratification and prevention of possible new events.However, the definition of the assessment protocol in the evaluation of patients with chest pain or other symptoms suspected for ACS is difficult. ACS requires early identification, adequate risk stratification and management: patients with ongoing chest pain and persistent ST-segment elevation (or new-onset left bundle branch block) require immediately recanalization by fibrinolytic treatment or primary angioplasty in patients with chest pain and EKG abnormalities suggesting acute ischemic heart disease, the strategy is to value the likelihood of ACS and to confirm or rule out myocardial necrosis, to alleviate ischemia and symptoms, to observe with serial EKG, to repeat measurements of markers of myocardial necrosis and to initiate appropriate therapy. However, suggested approach consistent of history, EKG and serum cardiac markers determination is time-consuming and not necessarily accurate: clinical presentation of ACS is often atypical, EKG abnormalities are not always present  and markRecent investigations have indicated that increases in several biomarkers upstream may provide earlier assessment of overall patient risk, help in identifying the adequate diagnostic and therapeutic management for each patient and allow for prevention of cardiac new events. It is now apparent that ACS shares a common anatomical substrate: pathological, angioscopic and biological observations have demonstrated that UA and acute myocardial infarction (AMI) are different clinical presentations that result from a common underlying patho-physiological mechanism, namely atherosclerotic plaque rupture or erosion, with different degrees of superimposed thrombosis and distal embolization .Creatine kinase (CK) and creatine kinase-MB (CK-MB) have a long history as the gold standard for AMI diagnosis. CK-MB is a CK isoenzyme, predominantly found in the myocardium. Its elevation occurs 4–6 h after the onset of myocardial necrosis and remains for 24–48 h. CK-MB sensitivity and specificity in detecting myocardial injury can be increased by serial testing . CK-MB iCardiac troponin T (cTnT) and cardiac troponin I (cTnI) are more sensitive and specific markers than CK-MB in detecting myocardial necrosis, and have become the preferred biomarkers for the diagnosis of AMI. They are also a useful prognostic indicator in patients with ACS. The superior clinical performance of troponin results from its higher sensitivity for smaller myocardial injury and its virtually total specificity for cardiac damage  and is cThese data demonstrate that troponin is a powerful marker for the hallmark of AMI and a useful tool in assessing risk and directing appropriate therapy that improves clinical outcome. Although cardiac troponins are specific of cardiac damage, they cannot be considered as the definitive marker of myocardial ischemic injury. Troponin release occurs due to non-ischemic cardiac damage, too, causing “false positive” elevations: myopericarditis, aortic dissection, aortic valve disease, hypertrophic cardiomyopathy, cardiac contusion or other trauma, tachy- or bradyarrhytmias, apical ballooning syndrome, congestive heart failure. Furthermore, elevation of cardiac troponin can also occur in non primary cardiac pathologies, such as acute neurological diseases, including stroke or sub-arachnoid hemmorrhage, infiltrative diseases, drug toxicity or toxins, burns affecting >30% of body surface area . An otheThere are a few methodological problems, in particular the lack of standardisation of assays for cTnI. Plasma levels of cTnI are associated with cardiac morbidity and mortality and have an independent prognostic value in patients with ACS  but therB-type natriuretic peptide (BNP) is preferentially produced and secreted in the left ventricle, although the right side of the human heart also synthesises and secretes BNP in response to disease . The preAvailable Commercial immunoassays measure BNP and its N-terminal inactive form NT-proBNP. The half-life of BNP is 20 min whereas NT-proBNP has a half-life of 120 min , which eBecause of the longest half-life NT-proBNP could be more sensitive than BNP in the diagnosis of the earliest phase of the left ventricular dysfunction . Many asThe clinical usefulness of cardiac natriuretic peptides  in the evaluation of patients with suspected heart failure, in prognostic stratification of patients with CHF, in detecting LV systolic or diastolic dysfunction and in the differential diagnosis of dyspnoea was confirmed . In geneAlthough originally BNP and NT-proBNP were considered biomarkers for heart failure only, now they are also considered biomarkers of myocardial ischemia. Elevated BNP and NT-pro-BNP levels have been observed in patients with stable coronary artery disease (CAD), in patients with UA  and duriThe therapeutic benefits that can derive from BNP and NT-proBNP assessment in ACS are not clear. In a substudy of the FRISC-II trial  which investigated the usefulness of NT-proBNP for identifying patients who might benefit from an early invasive strategy, a trend towards a better outcome of patients with NT-proBNP values in the highest tertile was observed. In the substudy of the PRISM trial, Heeschen et al. analysed the effect of glycoprotein IIb/IIIa inhibition with tirofiban with respect to NT-proBNP values . They foCRP is the most widely studied inflammation marker. CRP is a pentraxin, synthesized by liver after stimulation by cytokines, especially IL-6, IL-1β and TNF-α, in response to tissue injury or infection . CRP is The advantages of CRP as an inflammatory biomarker are related in part to analytic properties  and in part to its biological profile, including a long half-life (19 h). Liuzzo et al.   showed tA variety of cut-off points have been used in clinical studies of CRP in ACS, leaving some uncertainty about the optimal decision limits. In primary prevention studies the relationship is graded with a very low risk reported for CRP levels < 1.0 mg/l, intermediate risk between 1 and 3 and high risk above 3 mg/L . Liuzzo Available data support the use of CRP in conjunction with troponin and other traditional clinical tools as a prognostic marker in patients with ACS. Studies from Ridker’s group  demonstrThe relative and independent role of CRP in ACS in comparison to troponin and natriuretic peptides has been widely assessed and discussed. In 2003 Centre for Disease Control/American Heart Association  disseminThese guidelines consider cardiac troponin the best biomarker for initial evaluation and early risk stratification of ACS (both class IA), conversely natriuretic peptides (BNP and NT-proBNP) and CRP are not considered in the initial evaluation and have a class IIA (level of evidence A) recommendation for early risk stratification in ACS in addition to cardiac troponin, while their use a sole marker is discouraged. These guidelines appear well balanced and based upon the strong evidence in favor of troponin and, conversely, the lack of consistent data in favor of a clinical strategy based on natriuretic peptides and CRP.Placental growth factor (PIGF), a member of the vascular endothelial growth factor (VEGF) family, was shown to be profoundly upregulated in early and advanced atherosclerotic lesions . PIGF isIn 2004 Heeschen et al.  investigIn summary, although large trials are still needed to obtain PIGF validation and commercialization, it appears to have great potential as an independent biomarker for plaque disruption, ischemia and thrombosis and also as a novel anti-inflammatory therapeutic target in patients with CAD.Myeloperoxidase (MPO) is a hemoprotein (molecular mass ~140 kDa) composed of a pair of heavy and light chains. It is an enzyme that catalyzes the conversion of chloride and hydrogen peroxide to hypo-chlorite and has the optimum of activity at acid pH. It is stored in azurophilic granules of polymorpho-nuclear neutrophils and macrophages and is released into extracellular fluid in the setting of inflammatory process. MPO catalyzes activation reaction of several lysosomial proteins released as proenzymes from granulocytes  and has In summary, observations from studies that have investigated MPO activity, demonstrated MPO is more than a marker of oxidative stress and not only a marker of plaque instability. These pathophysiological characteristics are very interesting but more studies are needed to assess sensitivity and specificity of this biomarker in particular in heterogenous populations.Pregnancy-associated plasma protein (PAPP-A) is a high molecular mass (~200 kDa) glycoprotein typically measured during pregnancy for screening of Down syndrome . PhysiolPAPP-A blood levels seem to be an independent predictor of ischemic cardiac events and indicative of revascularization in patients with suspected MI but negative troponin: Lund J et al. found that PAPP-A plasma levels >2.9 mUI/l were associated with a risk of MI, death or revascularization 4.6-fold higher vs PAPP-A plasma levels <2.9 mUI/l . SimilarAlthough preliminary studies suggest that PAPP-A may be useful to evaluate patients with ACS, additional investigations will be necessary for better acceptance of PAPP-A as an independent biomarker for cardiovascular risk in ACS. It is difficult to measure PAPP-A present in atherosclerotic plaques by immunoassays because they are designed to detect PAPP-A present in pregnancy sera. The kinetics of PAPP-A release and the corresponding optimal sampling protocols in ACS remain to be determined . BecauseMetalloproteinases (MMPs) are a class of 24 endopeptidases that are physiologic regulators of the extracellular matrix . They arKai H et al.   measuredThe potential role of MMP-9 as a marker for risk stratification of patients with ACS was examined by Blankenberg et al. : they stBriefly, preliminary studies suggest that MMP-9 may be of value in evaluating ACS patients but additional investigations will be necessary for better acceptance of MMP-9 commercialization and clinical application.FABPs are low-molecular-mass proteins that are abundant in the cytoplasm of tissues having active fatty acid metabolism, including the heart, striated muscle, liver and intestine. FABPs are the major vehicle for cytosolic transport of long-chain unesterified fatty acids . MyocardH-FABP appears in blood soon after the onset of infarction, so it has been proposed as an early marker for the MI diagnosis . Its plaIn general, H-FABP was found to perform better than or similar to myoglobin in diagnosis of ACS , probablBecause H-FABP rapidly return to the normal range within 24 h after AMI, it can be also used to assess a recurrent infarction within 10 h after first AMI, possibly missed by CK-MB, cTnT and cTnI evaluation because plasma concentration of these markers returns more slowly to reference values. H-FABP has a renal clearence, therefore impaired renal function potentially impact its clinical utility; however, data from de Groot et al.  indicateThe rapid release of H-FABP can also be used for the detection of successful coronary reperfusion in patients with AMI . Both plSuzuki and coll.  have recFree fatty acids unbound to albumin (FFAu) were also evaluated for early identification of cardiac ischemia. FFAs are localized in the cytoplasm, bound to fatty acid binding protein (FABP) and represent the primary metabolic sources for myocardium. During hypoxia and ischemia, elevated blood cathecolamines increase FFAu concentration through adipose lipolyses activation. Increased non-esterified fatty acids/FFA levels have damaging effects on heart tissue and have been associated with an increased incidence of ventricular dysrhytmias and death in patients with AMI.Several investigators have preliminarily evaluated the sensitivity of this marker on admission to emergency room and have shown that FFAu elevation occurs before other, more traditional, markers of cardiac necrosis . In the P = 0.05). However, after adjustment for triglyceride concentrations, HDL-cholesterol, small and dense LDL, apolipoprotein B, and fasting plasma insulin, the relationship between plasma FFAu concentration and IHD development didn’t achieve statistical significance.FFAu have also been studied for risk stratification of ischemic heart disease (IHD). In the Paris Prospective Study I, increased plasma FFAu concentration were found to be an independent risk factor of sudden death, but not of fatal MI in a cohort of men without known ischemic cardiac disease . Pirro ePilz et al.  studied In conclusion, current data, although limited, suggest that monitoring FFAu concentrations in patients presenting with ischemia symptoms may provide an early indication of cardiac ischemia. Additional studies are needed to fully evaluate the true potential of this biomarker.Ischemia modified albumin (IMA), measured by the albumin cobalt binding test (ACB), has been shown to be a marker of myocardial ischemia. A multicenter study , involviThe positive predictive value of the ACB assay seems to be too low for use in ruling in ischemia. At present, whether patients with negative EKG results and necrosis markers, i.e. cardiac troponins, and a positive IMA result might benefit from early triage and intervention according to stratified pre-test probabilities is not known. In clinical practice, this lack of information can potentially lead to overtreatment of low-risk patients with a positive result.Recent findings suggest that IMA may be also useful in risk stratification of emergency chest pain patient . PeacockIMA appears to be indicative of oxidative stress and, therefore, might not be specific for cardiac ischemia. Increased IMA values are also found in patients with cancer, infections, end-stage renal disease, liver disease, and brain ischemia .In summary, many questions remain unanswered regarding IMA and the ACB test. The highest expected benefit of the test would be to rule out ACS in low to moderate pre-test probability conditions with negative myocardial necrosis markers and a negative EKG. However, the test seems to have limited specificity, with many false positives. Additional information, including a better understanding of IMA kinetics in the first hours after ACS and an optimum diagnostic cut-off value assessment, is needed for clinical validation of this new assay.Increasing evidence suggests that the use of biomarkers, reflecting distinct pathophysiological features such as oxidative stress, vascular inflammation, platelet activation, plaque destabilization and rupture along with more sensitive biomarkers of necrosis, may improve the traditional diagnostic and risk stratification approach in order to apply tailored treatment. However, no available biomarker offers ideal properties such as very early raise, very high sensitivity and specificity, easy and cheap assay. These observations suggest a multi-marker strategy, employing patho-biologically different biomarkers, that might help significantly in the identification of the “vulnerable” patient at risk for CHD, as suggested by a recent National Institutes of Health (NIH) panel . A multi


Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and oxidative stress, and may so represent the "metabolic memory". Furthermore, increased AGE accumulation is closely related to the development of cardiovascular complications in diabetes. This review article will focus on the clinical relevance of measuring AGE accumulation in diabetic patients by focusing on AGE formation, AGEs as predictors of long-term complications, and interventions against AGEs. Patients with diabetes have a mortality rate from cardiovascular disease (CVD) that is over twice compared to that in the general population . The AduThe original Maillard hypothesis on the formation of AGEs proposed that chemical modification of proteins by reducing sugars (glycation of proteins) in diabetes alters the structure and function of tissue proteins, precipitating the development of diabetic complications Fig.  7]. Gly. Gly7]. de novo formation, and absorption of AGEs from food or smoking may aggravate AGE accumulation in renal failure [Other pathways which may lead to AGE formation is through autoxidation of glucose by reactive oxygen species, and through carbonyl compounds ,10. In p failure -13.The characteristic fluorescence spectrum of AGEs at 440 nm upon excitation at 370 nm has classically been used to determine tissue AGE accumulation . Later bMoreover, blood and urine sampling of AGE do not necessarily reflect tissue AGE levels ,18. AfteNoninvasive techniques to analyze tissue AGE accumulation, such as lens or skin autofluorescence have also been described. For instance, lens autofluorescence  is significantly higher for diabetic patients than for age-matched control subjects, and the lens autofluorescence increases significantly with the progression of diabetic retinopathy . SeveralDiabetic patients have a clearly increased risk of cardiovascular morbidity and mortality. Both the DCCT and the UKPDS have shown that hyperglycemia contributes to the increased cardiovascular risk ,4. AGEs AGE levels are further related to other features of CVD, such as carotid stenosis and peripheral artery occlusive disease. AGE levels are higher in type 2 diabetic patients with peripheral artery occlusive disease compared to those without . FurtherAGEs are not only related to manifestations of CVD, but they also provide prognostic information. Table During long-term follow-up we observed that skin autofluorescence is a strong predictor of survival in diabetic patients ,36. IncrFigure Monnier et al first described the relation between AGE accumulation in skin collagen and the severity of long-term diabetic complications . BeissweRecently, we observed that AGE levels are related to both peripheral and autonomic neuropathy, even before clinical manifestations of neuropathy . FurtherInterventions possible against AGE formation and AGE-mediated damage are numerous. Intensive glycemic control in patients from the DCCT trial led to a lower risk for diabetic microvascular complications compared to conventional treatment . The lowAnother approach has been focused on the cleavage of already formed AGEs protein-protein crosslinks. Although AGE breakers have shown to break AGE-protein crosslinks in vitro, their beneficial effects in trials may not necessarily or exclusively be related to this breaking effect. Compounds like 4,5-dimethyl-3 phenacylthiazolium, also known as ALT-711, have been widely tested. AGE-breakers have been shown to break preformed AGE crosslinks, and to improve arterial compliance in a phase 2 clinical trial in elderly . CurrentWhile there are several pharmacological agents specifically aiming at AGEs, there are also "more common" agents that may also reduce AGE accumulation. Interestingly, antihypertensives, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers, reduce AGE accumulation in concert with the severity of diabetic nephropathy -62. MetfImportantly, in the past, clinical evaluation of AGE inhibition has been limited due to concern about long-term toxicity. An important aim of ongoing trials is to monitor unexpected side effects. Without important information on safety or clinical efficacy, trials have mostly focused on patients with long-term complications instead of analyzing primary prevention in diabetic patients.Table It is also important to stress that there is a major overlap in (increased) cardiovascular risk between persons with impaired (fasting) glucose tolerance and type 2 diabetes. The diagnosis of diabetes is also not a fixed diagnosis over time in e.g. an obese patient who manages to reduce weight considerably. If metabolic imbalances are stronger determining factors for cardiovascular risk than momentary glucose levels, or than a diagnosis of diabetes, this supports a role for assessing AGE accumulation.Measuring tissue AGE levels may be useful in monitoring and tailoring diabetes treatment. Many patients already use for example statins, ACE inhibitors, or metformine, which all may reduce AGE accumulation. Unfortunately, clinical trials evaluating the effect of specific AGE inhibitors or breakers are limited or still in progress. Some early trials were hampered by side effects of these pharmacological agents (e.g. vitamin B6 deficiency syndrome) .The question remains whether AGEs are a risk factor for CVD in the long run, or that AGEs are also a measure of current CVD activity. If AGE levels help to identify the diabetic patient with unstable cardiovascular disease, this may definitely increase the clinical relevance. Epidemiological studies investigating AGE levels as a marker of vulnerable plaques are lacking. Nevertheless, we recently observed that skin autofluorescence is an independent marker of acute myocardial infarction and it predicts major adverse cardiac events one year after acute myocardial infarction . Interestingly, skin autofluorescence was strongly related to markers of inflammation and oxidative stress.Finally, it is important for clinicians to critically appraise the value of new cardiovascular risk factors. As described by Morrow et al., the value of new risk factors may be structured around three issues: can we measure the risk factor, does it add new information and does it help to manage patients ? AGEs cain vitro research has shown that AGEs affect extracellular proteins and activate cytokine production and transcription factors via binding to AGE receptors. AGE accumulation closely correlates with the severity and predicts the development of cardiovascular complications. A variety of interventions against AGE accumulation, predominantly tested in preclinical contexts, appear to show beneficial effects on the development/progression of diabetic complications. Findings from current clinical trials, including feasibility studies, may further help in determining the relevance of AGE assessment in diabetes.AGEs have been implicated in the pathogenesis of long-term complications in diabetes. Animal and AGEs: advanced glycation endproducts; ALEs: advanced lipoxidation endproducts; RAGE: receptor for advanced glycation endproducts; CVD: cardiovascular disease; CHD: coronary heart disease; ACE: angiotensin converting enzyme; VCAM: vascular cell adhesion molecule; IMT: intima-media thickness; CML: carboxymethyllysine; HbA1c: glycated hemoglobin.Dr AJ Smit is co-founder of Diagnoptics, manufacturing the AGE-reader. Final approval and responsibility for the current review is with the first author R Meerwaldt.RM was responsible for writing the review article and final approval. TL was responsible for the design of the included studies (literature search). CZ was responsible for the literature search and revision review article. RT was responsible for the revision review article. JLH was responsible for the writing section on AGE formation. AS was responsible for drafting the review article.


The increasing prevalence of hypertension, owing to modern lifestyles and the increasing elderly population, is contributing to the global burden of cardiovascular (CV) disease. Although effective antihypertensive therapies are available, blood pressure (BP) is generally poorly controlled. In addition, the full benefits of antihypertensive therapy can only be realised when target BP is achieved. International guidelines and clinical trial evidence support the use of combination therapy to manage hypertension. In high-risk patients, such as those with coronary artery disease, diabetes and renal dysfunction, BP targets are lower and there is a need for intensive management with combination therapy to control BP and provide additional CV risk reduction benefits.Combinations of antihypertensive agents with different but complementary modes of action improve BP control and may also provide vascular-protective effects. Calcium channel blockers (CCBs) have been shown to be effective in combination with a range of antihypertensive drugs and in different patient populations. As part of a first-line combination strategy, CCBs can provide CV benefits beyond BP control, even in patients at increased CV risk. Benefits include protection against end-organ damage and serious CV events. Indeed, in major intervention trials, these benefits have already been clearly demonstrated. Ongoing studies will provide further data to support the clinical benefits of combination therapy as a first-line treatment approach. Implementation of this approach in clinical practice, together with adherence to global hypertension management guidelines will help ensure patients achieve and sustain BP targets, and reduce the risk of CV events. A literature search was conducted to identify recent randomised studies assessing CCB-based combination therapy strategies.Despite guideline recommendations, combination therapy is an underused strategy for the treatment of hypertension. Calcium channel blocker (CCB)-based combination strategies are effective and well tolerated when used with other classes of antihypertensive drugs, and should be considered a first-line option in hypertensive patients, particularly in those at high cardiovascular risk.Hypertension is one of the most important modifiable causes of premature death worldwide, and is estimated to cause 7.1 million premature deaths. Approximately one billion people worldwide have hypertension and the prevalence is predicted to increase dramatically in the next few years .Hypertension is a major risk factor for both cardiovascular (CV) and cerebrovascular morbidity and mortality , contribPatients with hypertension are also more likely to have associated CV risk factors ; for exaThe ultimate goal of hypertension management is to reduce CV morbidity and mortality by preventing end-organ damage –8. NumerAlthough effective therapies exist, current BP control is still below the ‘Healthy People 2010’ goal of 50%: only 34% of patients with hypertension have adequately controlled BP, 59% have treated but uncontrolled BP and 30% are unaware of their condition . Poorly Hypertension guidelines have traditionally recommended stepwise regimens to lower BP in patients with hypertension, beginning with lifestyle modification , and adding pharmacological intervention when lifestyle changes are insufficient ,6,7,12. Data from outcome studies show that several classes of drugs, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs) and thiazide-type diuretics, effectively lower BP and reduce the complications of hypertension ,13–16. HIn clinical practice, hypertension management varies greatly and many factors contribute to inadequate BP control, the most important include: patient non-compliance; acceptance of inadequate BP control by clinicians and reluctance to titrate the dose, switch to another drug or add another drug; and the fact that it is difficult to achieve adequate BP control with monotherapy in most patients, even when the dose is optimised . ResponsCompared with high-dose monotherapy, combination therapy is associated with fewer adverse effects. Guidelines advocate combination therapy with once daily treatment regimens that provide 24-h efficacy. The advantages of combination therapy include improved adherence to therapy  and miniCombination therapy was traditionally reserved as a third- or fourth-line approach in hypertension management ; howeverGuidelines recommend various two-drug combinations of different classes of antihypertensive agents based on data derived from controlled interventional trials, but advise that three or four drugs may be required depending on the patient's risk profile. Although older therapies such as diuretics and beta-blockers can effectively lower BP and are included as possible first-line combinations, they are associated with some disadvantages . For exaBy contrast, many studies have shown that newer antihypertensive agents, such as CCBs, ARBs and ACE inhibitors, provide additional benefits by reducing the incidence of CV events in patients with hypertension ,16,25,30Calcium channel blockers are used extensively in clinical practice and data from several clinical studies show that CCBs effectively and safely lower BP and reduce long-term CV risk in a wide range of patient populations ,35,38,39As CCBs have a different mode of action to commonly used inhibitors of the renin–angiotensin–aldosterone (RAAS) pathway (such as ACE inhibitors and ARBs), combination with these agents should provide synergistic or complementary effects, compared with using two agents that inhibit the same pathway. Indeed, in patients with newly diagnosed stage 1 or 2 hypertension or in patients with inadequate BP control after conventional low-dose monotherapy, low-dose combination therapy with CCBs and ARBs was found to provide better BP control than either high-dose monotherapy (p < 0.05 vs. either monotherapy) . FurtherIn the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies study, CCB and ACE inhibitor combination therapy with amlodipine and benazepril was significantly more effective in reducing SBP and pulse pressure in patients with severe systolic hypertension than either monotherapy (p < 0.0001) . SignifiData from outcome trials show that CCB therapy plus additional add-on treatment not only lowers BP but also improves patient outcomes. The Hypertension Optimal Treatment trial showed that intensive lowering of BP with CCB-based therapy (felodipine as baseline therapy with the addition of other antihypertensive agents according to a five-step regimen) was associated with a low rate of CV events . In the Data from ASCOT showed that CCB-based treatment is more effective than a beta-blocker-based regimen for reducing mortality and CV events . ASCOT cIn addition, there are several ongoing studies to determine the optimal antihypertensive combination therapy with the most favourable safety profile for lowering BP and protecting against CV events. The Combination Therapy of Hypertension to Prevent Cardiovascular Events study is a multicentre trial assessing CV outcomes in hypertensive patients treated with various drug combinations including ARBs, beta-blockers or diuretics in combination with a CCB (benidipine) . The AvoSeveral other large, randomised clinical studies have investigated the use of antihypertensive combination therapies in high-risk patient populations, including those with impaired renal function, diabetes or CAD, in whom BP is more difficult to control to target levels. These will be discussed in more detail in the following sections.There is strong evidence to show that hypertension is probably the most important risk factor for stroke  – the riThe safety and efficacy of CCBs have also been demonstrated in several high-risk patient populations, such as those with impaired renal function, diabetes or CAD.In hypertensive patients at high CV risk, renal dysfunction has been shown to be an important predictor of CV risk and to act as a prognostic marker of progression to CVD . FurtherACTION examined the benefits of additional nifedipine GITS intervention in patients with stable angina and CAD who were receiving best practice therapy. Almost 40% of the patients in ACTION had evidence of renal dysfunction ,55, and In the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT), patients with mild-to-moderate hypertension received nifedipine GITS or the diuretic combination co-amilozide, with the addition of atenolol  followed by addition of any other antihypertensive drug (other than CCBs or diuretics) if BP targets were not achieved. The study showed that, in hypertensive patients at high CV risk, renal function was better preserved with nifedipine GITS than with diuretics (p < 0.0001). The improved renal function with nifedipine GITS was indicated by better preserved creatinine clearance, which is a marker of renal function, and fewer patients treated with nifedipine GITS had progressive renal deterioration compared with those treated with co-amilozide ,53.post hoc analysis of the changes in estimated glomerular filtration rate with a CCB (amlodipine), a diuretic  and an ACE inhibitor (lisinopril). In this trial, the incidence of end-stage renal disease was similar for all three treatment arms, but estimated creatinine clearance was significantly better preserved with amlodipine than with chlorthalidone or lisinopril  than in patients with primary hypertension ,6. HowevSeveral studies have shown that CCB-based combination therapy can improve clinical outcomes in individuals with diabetes. In INSIGHT, nifedipine GITS reduced the risk of all-cause mortality in patients with diabetes compared with those without diabetes and reduced the frequency of new cases of diabetes compared with diuretic therapy . FurtherIn ACTION, more than 50% of patients had inadequately controlled BP at baseline, despite receiving best practice therapy at study entry . At baseFurther analysis of the ACTION results revealed even greater benefits in the subgroup of patients with inadequate BP control at baseline . There wHypertension is a multifactorial disease, so disruption of a single physiological pathway is often insufficient to control BP. Therefore, a combination of two drugs with different but complementary modes of action is often needed to achieve effective BP control. This is supported by hypertension guidelines, which highlight the need for drugs to be combined effectively and emphasise the benefits of drugs with different mechanisms of action on a multi-regulated variable such as BP ,6,7.Dihydropyridine CCBs and inhibitors of the RAAS pathway  are widely used in patients with CVD. They have complementary mechanisms of action so, when used in combination, have synergistic effects on pathological changes in the vasculature and end organs, providing benefits in addition to BP control.Calcium channel blockers primarily affect the cellular interactions of endothelial cells, smooth muscle cells, monocytes and thrombocytes, which have key roles in the early phases of atherosclerosis development. There is also evidence to show that CCBs affect the nitric oxide system in endothelial cells. Several studies have shown that endothelium-dependent relaxation, which is impaired in individuals with hypertension, can be restored by treatment with dihydropyridine CCBs –67. CCBsBoth guideline recommendations and clinical trial evidence support the use of combination therapy in managing hypertension, particularly in patients at increased risk of CV events and those for whom BP targets are lower because of the need for intensive management of additional risk factors, such as those with CAD, metabolic syndrome, diabetes or renal dysfunction. In a large proportion of patients, it is difficult to lower BP to target levels using antihypertensive monotherapy, so more intensive intervention, specifically combination antihypertensive therapy, is often required. Clinical studies have proved the efficacy of CCB-based combination strategies in a wide range of high-risk patient groups.Combination therapy with antihypertensive agents that have different but complementary mechanisms of action not only avoids unnecessary drug interactions and adverse events, but also maximises the benefits of agents that have additional effects beyond BP lowering. For example, there is evidence to show that the combination of CCBs and ARBs provides end-organ protection through synergistic mechanisms. CCBs are effective with all other antihypertensive agents, and this flexibility makes them ideal as part of a first-line combination strategy to achieve target BP and provide additional CV benefits, without compromising safety in patients at increased CV risk.In clinical practice, there is still much inconsistency with regards to stepwise treatment of patients and the decision to increase drug dose, switch therapy or add another drug. Combination therapy may still be considered a last resort in the treatment of hypertension and be rarely used as initial or first-line therapy. The treatment paradigm is now changing and more patients are being treated in line with guideline recommendations, which focus on overall CV risk and therefore recommend multiple-drug strategies early in the course of treatment.Ongoing studies will provide further data to support the benefits of antihypertensive combination therapy on clinical outcomes when used as a first-line strategy. Increased efforts to use combination therapy much earlier in the course of treatment and increased adherence to global guidelines will ensure patients achieve and sustain BP control in addition to reducing the risk of CV events.