Antiplatelet Treatment in Essential Hypertension

Curr Hypertens Rep (2015) 17:24 DOI 10.1007/s11906-015-0536-2

NOVEL TREATMENTS FOR HYPERTENSION (T UNGER, SECTION EDITOR)

Antiplatelet Treatment in Essential Hypertension: Where Do We Stand? Eugenia Gkaliagkousi & Eleni Gavriilaki & Stella Douma

# Springer Science+Business Media New York 2015

Abstract Antiplatelet agents represent a cornerstone in the management of patients at increased cardiovascular risk. Essential hypertension is considered a major public health problem leading to increased cardiovascular morbidity and mortality. The majority of patients with essential hypertension exhibit also additional cardiovascular risk factors and present with increased platelet activation. Despite recent innovations in the field of antiplatelet treatment and the introduction of novel agents, the role of antiplatelet treatment in patients with essential hypertension remains understudied. This review aims to shed light on novel experimental and clinical data in the evolving field of antiplatelet treatment in essential hypertension. In particular, recent data regarding aspirin, clopidogrel, novel P2Y12 inhibitors, and other agents with potential antiplatelet effects are critically reviewed. Keywords Antiplatelet treatment . Aspirin . Clopidogrel . Ticagrelor . Prasugrel . Essential hypertension Introduction Antiplatelet agents represent first-line treatment of atherothrombotic disease. Aspirin and/or clopidogrel have This article is part of the Topical Collection on Novel Treatments for Hypertension E. Gkaliagkousi 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece E. Gavriilaki : S. Douma 3rd Department of Internal Medicine, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece E. Gavriilaki (*) 3rd Department of Internal Medicine, Papageorgiou Hospital, Ring Road Nea Eukarpia, 56403 Thessaloniki, Greece e-mail: [email protected]

been widely studied and used in primary and secondary prevention of cardiovascular and cerebrovascular events. However, hyporesponsiveness to aspirin or clopidogrel that leads to an increased risk of thromboembolic events has raised concerns in terms of proper patient management. Over the last years, intensive research in the field has also introduced novel antiplatelet agents, such as novel P2Y12 inhibitors and GPIIb/ IIIa inhibitors, with promising features. Increased cardiovascular and cerebrovascular morbidity and mortality are commonly associated with the diagnosis of essential hypertension [1]. The latter is considered a major public health problem affecting almost 1 billion people worldwide [2]. The majority of patients with essential hypertension exhibit also additional cardiovascular factors that lead to a greater total cardiovascular risk [3]. The increased thrombotic tendency observed in patients with essential hypertension accounts for more than 7.5 million deaths annually [4]. Among factors sustaining the prothrombotic state in essential hypertension, increased platelet activation has been long recognized as a trigger of the hypercoagulable state. Beyond that, platelet activation represents a promising therapeutic target in patients with essential hypertension [5]. In this context, we aimed at updating current knowledge in the evolving field of antiplatelet treatment in patients with essential hypertension. To that reason, we have performed a Pubmed search for studies published later than 2009 using the terms blood pressure, essential hypertension, antiplatelet, platelet, aspirin, clopidogrel, and responsiveness. Data presentation has been organized according to different antiplatelet agents.

Aspirin Recent data on the use of the cyclo-oxygenase-1 inhibitor aspirin in essential hypertension are mainly provided by a

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2011 Cochrane systematic review [6••]. This review primarily analyzed results of four older randomized control trials: hypertension optimal treatment (HOT) [7], TPT [8], CARPIE [9], and a study by Huynh et al. [10]. Among them, the only trial designed for patients with essential hypertension was the HOT trial. Based on their analysis, the authors concluded that the usefulness of aspirin in secondary prevention is unquestionable. As regards primary prevention, although aspirin provided benefits, it was also associated with an increased risk of major hemorrhage [6••]. Nevertheless, the increased risk of major hemorrhage may potentially be outweighed by benefits in specific populations. A recent post hoc analysis of HOT study has shown that aspirin results in greater absolute reduction of major cardiovascular events and mortality in hypertensive patients with chronic kidney disease compared to patients with normal renal function [11•]. In accordance with these findings, the latest European Society of Hypertension guidelines recommended the use of low-dose aspirin in secondary prevention and in controlled hypertensives with reduced renal function or high cardiovascular risk [3]. The benefits of aspirin in patient with diabetes remain unclear according to the latest guidelines [3]. However, diabetic patients are stratified at very high cardiovascular risk even with high normal blood pressure levels (130–139/ 85–89 mmHg) [3]. In an effort to address the issue of antiplatelet treatment in primary prevention of diabetic patients, the American Heart Association (AHA), American Diabetes Association, and American College of Cardiology Foundation issued relevant guidelines in 2010 [12]. According to these guidelines, low dose of aspirin is recommended as primary prevention in diabetic patients at increased cardiovascular risk and might be considered for patients at intermediate risk [12]. Over the last years, concerns have been raised regarding hyporesponsiveness to aspirin. Almost one third of patients receiving aspirin have been identified as resistant to treatment by several studies [13–15]. Early studies have investigated the sensitivity and specificity of different assessment methods (light transmission aggregometry, PFA-100, VerifyNow, Multiplate analyser) in different populations [16, 17]. Despite detected differences, all methods are considered reliable in reflecting aspirin responsiveness. According to two older meta-analyses of available data, aspirin hyporesponsiveness has been associated with increased risk of recurrent ischemic events [13, 15]. However, it should be noted that these studies involved mainly high-risk patients with acute coronary syndromes or vascular interventions shortly after initiation of antiplatelet treatment. In a recent study, Reny et al. investigated whether assessment of antiplatelet hyporesponsiveness has an incremental predictive value in terms of predicting future cardiovascular events in patients with stable cardiovascular disease over and above traditional cardiovascular risk factors. The authors implemented both aggregation-based as well as biochemical-specific assays to estimate antiplatelet

hyporesponsiveness for both aspirin and clopidogrel. They concluded that traditional cardiovascular risk factors were associated with recurrence of major adverse cardiovascular events but aspirin and clopidogrel hyporesponsiveness had no additional predictive power [18••]. Therefore, although present in a relatively high percentage, aspirin hyporesponsiveness, at least in stable cardiovascular populations, cannot be used as a risk stratification tool to improve prediction of future events. Another interesting research field involves the determination of clinical factors predisposing to aspirin resistance. Essential hypertension is associated with aspirin resistance in various clinical settings. Indeed, according to a recent study, hypertension and systolic blood pressure levels were bivariately associated with aspirin resistance in patients with stable coronary artery disease (CAD), without adjusting for other confounding factors [19]. This finding was also evident in a previous study confirming an independent association between hypertension and aspirin non-responsiveness in a heterogeneous group of patients receiving aspirin [20]. However, only diabetes and dyslipidemia were associated with aspirin resistance in patients with unstable CAD [21]. Of note, we should bear in mind that results vary according to methods used to detect platelet reactivity [22], time period from antiplatelet treatment initiation, and patient characteristics.

Clopidogrel Clopidogrel is an inactive compound converted into an irreversible P2Y12 receptor antagonist by enzymes of the cytochrome P450 system, mainly CYP2C19. Recent experimental studies have revealed pleiotropic effects of clopidogrel on hypertensive target organ damage. More specifically, clopidogrel treatment prevented angiotensin II-induced cardiac inflammation and fibrosis (cardiac remodeling) in mouse models through inhibition of platelet activation [23]. In addition, clopidogrel treatment prevented vascular remodeling and improved endothelial function in hypertensive rats [24•]. Interestingly, these effects were not mediated by P2Y12 receptors [24•]. Clopidogrel P2Y12 receptor blockade protected against impairment of autoregulatory behavior and renal vascular injury in similar angiotensin II-induced hypertensive models [25]. Despite encouraging experimental results, clopidogrel use in patients with essential hypertension has not been properly investigated in clinical trials. Clopidogrel is primarily used in secondary prevention of cardiovascular disease [26]. Recent ΑΗΑ guidelines for antiplatelet treatment in stable ischemic heart disease recommended treatment with clopidogrel when aspirin is contraindicated and combination treatment with aspirin and clopidogrel for certain high-risk patients, such as patients with prior MI, ischemic stroke, or symptomatic peripheral arterial disease [27].


Combination of aspirin and clopidogrel is also considered substantial after transcatheter aortic valve replacement [28], percutaneous coronary intervention (PCI), after fibrinolytic therapy in patients with ST segment elevation myocardial infarction (STEMI) [29] and in patients with unstable angina or NSTEMI at medium or high risk from presentation up to 12 months [30, 31]. Interestingly, a recent randomized study in patients taking oral anticoagulants undergoing PCI has shown that clopidogrel without aspirin is associated with reduction in bleeding and no increase in thrombotic events as compared to the combination of aspirin and clopidogrel [32]. Aspirin and clopidogrel combination as an alternative antithrombotic treatment of patients with nonvalvular atrial fibrillation has been replaced by the novel oral anticoagulant agents (direct thrombin and factor Xa inhibitors). The role of the novel anticoagulant agents will not be further addressed in this review that aims to focus on antiplatelet treatment. Regarding clopidogrel, the most recent AHA guidelines on patients with atrial fibrillation recommended its use only after coronary revascularization in patients with CHA2DS2-VASc score greater than 2, concurrently with oral anticoagulants but without aspirin [33]. Likewise, recent AHA guidelines on primary prevention of stroke emphasized on the role of novel anticoagulants in patients with atrial fibrillation and aspirin as the only suitable antiplatelet agent in patients with high cardiovascular risk [34]. In terms of secondary prevention, AHA guidelines did not recommend clopidogrel and aspirin combination for patients with ischemic stroke or transient ischemic attack (TIA) [35]. In favor of this recommendation, a randomized controlled trial in patients with recent lacunar stroke showed no benefits of the combination with an increased risk of bleeding [36]. However, another randomized trial documented that patients with TIA or minor stroke treated within 24 h after the onset of symptoms with the combination of clopidogrel and aspirin presented with a reduced risk of stroke in the first 90 days without an increased risk of hemorrhage [37]. This controversial question might be answered by a most recent meta-analysis in the field demonstrating that short-term combination is effective and safe for high-risk stroke patients, whereas long-term combination is associated with an increased bleeding risk [38••]. Similar to aspirin, clopidogrel non-responsiveness has been calculated to 25 % and associated with an increased risk of ischemic events according to a meta-analysis by Combescure et al. [39]. High on treatment platelet reactivity has also been shown as an independent predictor of cardiovascular morbidity and mortality in patients receiving clopidogrel after elective percutaneous coronary intervention [40, 41]. However, the results from the meta-analysis by Reny et al. [18••], negating the clinical impact of antiplatelet drug response status, were also evident for clopidogrel treatment. It should be noted again that the assay heterogeneity highly influences the results

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among different studies, as documented in a study by Gremmel et al. where the factors influencing on-treatment platelet reactivity were assay dependent [42•]. Nevertheless, a number of studies have explored the factors contributing to high clopidogrel resistance. Genetic factors linked with decreased clopidogrel response have been widely studied. First, the cytochrome CYP2C19*2 gene polymorphism has attracted the Food and Drug Administration’s attention that issued a “boxed warning” leaving the issue of genetic testing up to the individual physician [43]. Most recent meta-analyses on this topic confirmed that CYP2C19*2 polymorphism is associated with clopidogrel resistance [44] and adverse clinical events [45]. AHA encourages genotyping if results of testing may alter management in a Class IIb recommendation as no prospective studies of the genotype-guiding treatment exist [30]. Rationale and design of such studies, as the POPular Genetics study, have been recently announced [46•]. Clopidogrel metabolism by CYP2C19 also affects pharmacodynamic interactions with drugs metabolized by the same cytochrome, especially proton pump inhibitors (PPIs). Although results are conflicting, more recent studies support the concomitant administration of clopidogrel with PPIs when the latter are indicated [47, 48]. In accordance with this evidence, the recent expert position paper on antithrombotic therapy and PPIs suggested the use of PPIs with weaker inhibition of CYP2C19 in combination with clopidogrel [49]. Second, carriers of the P-selectin gene (SELP) Pro715 allele were characterized by lower levels of soluble P-selectin and P2Y12 receptor reactivity [50]. Paraoxonase 1 (PON1) enzyme activity which is modulated by the PON1-Q192R variant (rs662) has been suggested a modulator of bioactivation. However, in a meta-analysis, the PON1Q192R polymorphism had no impact on major cardiovascular events or response to clopidogrel [51]. In addition, a most recent study has introduced the easily accessible mean platelet volume as a marker of clopidogrel response in patients with acute coronary syndromes [52] An interesting finding for patients with essential hypertension is that treatment with calcium channel blockers has been associated with decreased platelet inhibition by clopidogrel [53, 54]. Among other clinical factors, type 2 diabetes has been implicated in impaired clopidogrel response [55, 56]. Other factors include race, female, gender [56], and hypertension [19].

Novel Agents Novel P2Y12 Inhibitors The third generation thienopyridine prasugrel is an inactive compound metabolized mainly by a single CYP2C19 step into active metabolite that indirectly and irreversibly binds to the P2Y12 receptor. The newer P2Y12 inhibitor ticagrelor is

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an active compound that directly and reversibly inhibits this receptor [57]. AHA guidelines did not recommend the use of newer P2Y12 inhibitors in patients with stable ischemic heart disease due to the lack of relevant data [27]. Nonetheless, recent studies indicate that use of prasugrel or ticagrelor in certain patients with stable CAD is efficient [58],[59, 60]. As regards patients with STEMI, the use of prasugrel or ticagrelor was recommended in combination with aspirin with an equal class recommendation as that of clopidogrel [29]. Prasugrel was also recommended after PCI or 24 h after fibrinolytic therapy in STEMI patients. However, prasugrel was not recommended in patients with a history of stroke or TIA. In patients with unstable angina or NSTEMI continued use of prasugrel or ticagrelor was recommended for at least 12 months in post-PCI patients treated with coronary stents [30]. Interestingly, ticagrelor was recommended in preference to clopidogrel for patients undergoing an early invasive or ischemia-guided strategy [31]. The latter recommendations were primarily based on the favorable effects of prasugrel on cardiovascular endpoints observed in the TRITON-TIMI 38 study, which were however neutralized in terms of mortality by increased fatal bleeding [61]. Ticagrelor also proved its efficacy in cardiovascular outcomes and mortality in patients with acute coronary syndromes in the PLATO study [62], including the sub-study of patients with previous stroke or TIA [63•]. A minor consideration in ticagrelor treatment is mild to moderate dyspnea caused in some patients [60, 62]. The newer P2Y12 inhibitors overcome some obstacles of clopidogrel treatment. First, concomitant use of PPIs does not significantly affect platelet inhibition of prasugrel or ticagrelor [49]. In particular, the most recent DOSAPI study in patients with stable CAD showed no interaction between lansoprazole and prasugrel in contrast to that observed with clopidogrel [64•]. Previous studies had suggested the low impact of PPIs use on platelet reactivity with prasugrel [47]. Ticagrelor treatment was also not associated with higher platelet reactivity in patients receiving PPIs [62]. Second, CYP2C19 polymorphism seems not to significantly affect prasugrel efficiency [65]. In addition, prasugrel pharmacodynamics and pharmacokinetic parameters are affected neither by CYP2C19 nor by PON1 and ABCB1 polymorphisms [66]. In cost-effectiveness analysis, ticagrelor is the most cost-effective option for patients with acute coronary syndromes [67, 68]. Third, ticagrelor has been recently reported to effectively substitute clopidogrel in a case of severe clopidogrel-induced neutropenia. Unlike prasugrel, ticagrelor’s structural differences from other thienopyridines suggest its potential role as an alternative treatment in clopidogrel neutropenia or even allergy [69].


GPIIb/IIIa Inhibitors GPIIb/IIIa inhibitors are restricted to intravenous administration in high-risk patients with acute coronary syndromes [70] and will not be further analyzed in this review.

Other Agents with Potential Antiplatelet Effects Renin Angiotensin System Inhibitors Renin angiotensin system (RAS) inhibitors used as first-line antihypertensive agents include angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Earlier studies have implicated agents from both classes, mainly perindopril and losartan, in potential antiplatelet effects in patients with essential hypertension [71, 72]. Further experimental studies have confirmed the antiplatelet properties of losartan [73, 74]. In the clinical setting, losartan proved its antithrombotic effects in hypertensive patients with atrial fibrillation [75]. Beyond losartan, valsartan presented also with antiplatelet effects in a randomized study of hypertensive patients [76]. More recently, antihypertensive treatment with valsartan attenuated the exaggerated and prolonged platelet activation following acute exercise in untreated patients with essential hypertension [77]. On the contrary, enalapril and losartan failed to reduce platelet activation at rest and following exercise in a study of hypertensive patients [78] with several methodological concerns [79]. Proliferator-Activated Receptor (PPAR) Agonists PPARs represent a family of three nuclear receptor isoforms (α, β/δ, and γ). Increasing amount of evidence points towards PPAR-mediated antiplatelet actions [80]. Agents that activate PPAR such as statins, fibrates, thiazolidinediones, and nifedipine exhibit antiplatelet effects [80]. In particular, nifedipine which belongs to calcium channel blockers has been recently shown to enhance PPAR-β/-γ activity and through upregulation of platelet activation-related signaling pathways, exert antiplatelet actions [81•, 82].

Future Perspectives In conclusion, antiplatelet treatment in patients at increased cardiovascular risk represents a continuously evolving research field. Taking into account the increasing prevalence of essential hypertension, further clinical trials specifically designed to address the issue of antiplatelet treatment in essential hypertension are needed. The role of clopidogrel and the advantages of newer P2Y12 inhibitors remain to be further clarified.


On the other hand, physicians dealing with hypertensive patients should bear in mind that adequate hypertension control may be one of the first and most crucial steps in hypertension management. In addition, total cardiovascular risk assessment and comorbidities optimal management is of great importance. Specific pleiotropic effects of RAS inhibitors or nifedipine remain to be proven in future studies of platelet activation in hypertensive patients aiming at determining the treatment of choice. Compliance with Ethics Guidelines Conflict of Interest Eugenia Gkaliagkousi, Eleni Gavriilaki, and Stella Douma declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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