American Journal of Cardiovascular Drugs

Perindopril, an ACE inhibitor, and amlodipine, a dihydropyridine calcium channel blocker, are established antihypertensive agents with complementary mechanisms of action. Recently, a once-daily, orally-administered, fixed-dose combination (FDC) of perindopril arginine plus amlodipine besylate (Prestalia®; hereafter referred to as perindopril/amlodipine FDC) was approved in the USA for the treatment of hypertension. This article reviews the efficacy and tolerability of perindopril/amlodipine FDC and briefly summarizes the agent’s pharmacologic properties. As demonstrated in short-term randomized controlled trials, perindopril/amlodipine FDC was significantly more effective in reducing blood pressure (BP) than monotherapy with either of the component drugs, and it appeared to be more effective than an up-titration scheme using valsartan and valsartan/amlodipine. The FDC agent was generally well tolerated, with the most common adverse events (peripheral edema, cough, headache, and dizziness) being consistent with the well-defined tolerability profiles of the individual component drugs. Furthermore, perindopril/amlodipine FDC was associated with a numerically lower incidence of peripheral edema compared with amlodipine monotherapy. Thus, perindopril/amlodipine FDC represents a useful option for the treatment of hypertension, including as initial therapy for patients likely to require multiple drugs to achieve their BP targets.

Cardiovascular disease continues to be the most common cause of mortality in women in the USA. As a result, greater emphasis has been placed on preventive measures. Studies examining the role of aspirin and HMG-CoA reductase inhibitors (statins) have shown important clinical differences in men versus women in the preventive realm. This has led to inconsistent recommendations by guideline committees and clinicians alike. This review presents a summary of the past and current guidelines. In addition, important clinical trials influencing current era practice are also discussed. Both strengths and limitations of these studies are described in detail, along with recommendations regarding future directions and the scope of aspirin and statin use for primary and secondary prevention of cardiovascular disease.

Alirocumab (Praluent®) is a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered via subcutaneous injection every 2 weeks. Across ten phase III studies from the ODYSSEY clinical trial program in patients with heterozygous familial hypercholesterolemia (heFH) or nonfamilial hypercholesterolemia (nonFH), including some with mixed dyslipidemia, subcutaneous alirocumab 75 or 150 mg every 2 weeks was significantly more effective with regard to reducing low-density lipoprotein-cholesterol (LDL-C) over 24 weeks than comparator agents (i.e. matching placebo, once-daily oral ezetimibe, or modified oral statin therapy), including when administered as monotherapy or in combination with statin therapy, and when administered with non-statin lipid-lowering therapy (LLT) in patients with statin intolerance. Alirocumab provided sustained LDL-C-lowering efficacy over 52–78 weeks’ treatment in longer-term trials, and was associated with significantly favorable effects on several other lipid parameters, including non-high-density lipoprotein-cholesterol (non-HDL-C) and lipoprotein (a) [Lp(a)]. Alirocumab was generally well tolerated in phase III trials, with no apparent increase in muscle-related adverse events compared with placebo. Thus, alirocumab is a valuable emerging option for use in patients with hypercholesterolemia, particularly patients with statin intolerance or inadequately-controlled LDL-C despite statin therapy; however, more data are needed to establish its potential cardiovascular benefits.

Patients with chronic kidney disease (CKD) and ischemic heart disease (IHD) have strikingly high mortality rates. In the general population, there has been a reduction in the mortality and morbidity rates for IHD through the implementation of effective risk-factor-reduction programs and better interventions for patients with established IHD. No such trend has been observed in patients with end-stage kidney disease. This review article addresses the following topics: (i) epedemiology, pathogenesis, clinical CKD patients with IHD; (ii) diagnostic modalities for IHD and their limitation in CKD patients; (iii) medical treatment options and revascularization strategies for these high-risk patients; and (iv) optimal cardiovascular risk management. Generally, in CKD patients with IHD an aggressive approach to IHD is warranted, a low threshold for diagnostic testing should be employed, and awaiting a clinical trial targeting these patients they should be considered for all proven strategies to improve outcomes.

Ambrisentan, an orally active, highly selective antagonist of the endothelin-1 type A receptor, is indicated for the treatment of pulmonary arterial hypertension (PAH). It has a low potential for drug-drug interactions and requires only once-daily administration. Three months’ treatment with ambrisentan 2.5–10 mg/day significantly improved exercise capacity, as determined by the distance walked in 6 minutes (6MWD; primary outcome measure), compared with placebo in two double-blind, multicenter studies in patients with PAH (ARIES-1 [n = 202] and -2 [n = 192]). A decrease in dyspnea and a delay in clinical worsening were among the improvements in secondary outcomes generally observed with ambrisentan versus placebo. In ARIES-E, a 2-year extension of ARIES-1 and -2, approved dosages of ambrisentan (5 and 10 mg/day) were associated with a sustained improvement in 6MWD, a generally sustained improvement in dyspnea, and a low risk of clinical worsening and of death. Six months’ treatment with ambrisentan 5 mg/day significantly improved 6MWD (primary outcome measure) and dyspnea relative to baseline in an open-label, non-comparative, multicenter study in a diverse population of patients with PAH or non-PAH forms of pulmonary hypertension (ARIES-3 [n=224]). Ambrisentan was associated with a low risk of clinical worsening and of death. Ambrisentan treatment was generally well tolerated in the various ARIES trials. All available pre-registration and post-marketing data indicate the drug poses only a very low risk of liver injury; the ‘black box’ warning regarding potential liver injury has been removed from the US prescribing information for ambrisentan.

A bioequivalent formulation of intravenous epoprostenol containing the excipients arginine and sucrose (epoprostenol AS) (Veletri®, Caripul®) is approved in the USA, UK, and other countries for the treatment of pulmonary arterial hypertension (PAH), and has improved thermal stability compared with epoprostenol containing glycine and mannitol (epoprostenol GM) (Flolan®). Epoprostenol, a synthetic prostacyclin, is a potent pulmonary vasodilator. Epoprostenol GM was originally approved for use as a long-term continuous infusion in patients with PAH nearly 20 years ago in the USA; however, this formulation has limited stability at room temperature, and requires the use of cooling or frequent medication changes during administration. The prolonged thermal stability of epoprostenol AS compared with epoprostenol GM allows for its extended administration at room temperature and/or refrigerated storage of prepared solutions. This article summarizes the pharmacology of epoprostenol AS and reviews its therapeutic use in adult patients with PAH. In clinical trials, epoprostenol AS provided sustained efficacy in terms of hemodynamic and symptomatic outcomes, and was generally well tolerated after transitioning from stable epoprostenol GM therapy and during an open-label extension study. Furthermore, there was a significant increase in the treatment convenience with epoprostenol AS compared with epoprostenol GM. Therefore, epoprostenol AS is a valuable therapeutic option that has the potential to overcome some of the limitations of long-term intravenous epoprostenol therapy in patients with PAH.