Angiotensin Receptor Blockers Worsen Renal Function and Dyspnea on Ticagrelor: A Potential Ticagrelor‐Angiotensin Receptor Blocker Interaction?

Ticagrelor is a new antiplatelet agent that was pitted against clopidogrel in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Because ticagrelor is the first oral, reversible, twice‐daily agent, sufficient information on drug interactions is not available. Our objective was to ascertain the safety of ticagrelor with other common medications. The US Food and Drug Administration Complete Response Review indicates that renal adverse events (AEs) and renal function AEs were higher in ticagrelor‐treated patients who were concomitantly treated with angiotensin receptor blockers (ARBs) >50% of study days compared to ticagrelor‐treated patients who did not receive ARBs >50% of study days. Clopidogrel‐treated patients showed a trend for an increase in adverse renal events with ARB use. However, this was not as pronounced as that observed with ticagrelor. Dyspnea was also significantly increased in patients on concomitant ticagrelor‐ARB compared to ticagrelor without concomitant ARB and clopidogrel (21.4% vs 14.6% vs 9.9%, respectively) as well as angioedema (0.15% vs 0.09%). Furthermore, in patients with a baseline estimated glomerular filtration rate (eGFR) <30 mL/min, the risk of major bleeding, death, and renal failure was increased in patients on ticagrelor compared to patients on clopidogrel. In patients on ticagrelor, ARBs significantly increased the frequency of renal related AEs, renal function AEs, and dyspnea. Moreover, in patients with a baseline eGFR <30 mL/min, the risk of major bleeding, death, and renal failure was increased in patients on ticagrelor compared to patients on clopidogrel. Dr. Serebruany is listed as an inventor for the US patent application: TREATING CARDIAC ARRHYTHMIAS, HEART FAILURE, PERIPHERAL ARTERY DISEASE AND STROKE WITH CYCLOPENTYL‐TRIAZOLO‐PYRIMIDINE OR DERIVATIVE THEREOF (USN 61/253,829) assigned to HeartDrug? Research, and received funding for research studies with clopidogrel, and consultant fees from both clopidogrel and ticagrelor manufacturers.     

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Promising Medication for Chronic Obstructive Pulmonary Disease?

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a complex disorder that primarily affects the lungs and is characterized not only by local pulmonary, but also by systemic inflammation which promotes the development of extrapulmonary and cardiovascular co-morbidities. Angiotensin converting enzyme (ACE) inhibitors and ARBs (angiotensin receptor blockers) are widely used drugs in the treatment of cardiovascular diseases, with growing evidence suggesting potential benefits in COPD patients. The purpose of this review is to describe the correlation of renin–angiotensin system (RAS) with COPD pathophysiology and to present the latest data regarding the potential role of RAS blockers in COPD.     

Dual-Acting Angiotensin Receptor–Neprilysin Inhibition

Lowering blood pressure by pharmacologic intervention reduces the incidence of cardiovascular events. Nevertheless, despite the widespread availability of effective antihypertensive medications, the vast majority of hypertensive patients worldwide continue to have inadequate blood pressure control. The development of new antihypertensive drugs could contribute to improving the hypertension control rate, and the blockade of new pathophysiologic pathways involved in blood pressure regulation would offer additional benefits. The dual inhibition of the angiotensin II receptor and neprilysin could provide clinical benefits in a range of cardiovascular diseases, including hypertension and heart failure.     

Fixed-Dose Combinations of Renin–Angiotensin System Inhibitors and Calcium Channel Blockers in the Treatment of Hypertension: A Comparison of Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors

Fixed-dose combinations (FDCs) of different regimens are recommended in guidelines for the treatment of hypertension. However, clinical studies comparing FDCs of angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) and angiotensin-converting enzyme inhibitor (ACE inhibitor)/CCB in hypertensive patients are lacking.Using a propensity score matching of 4:1 ratio, this retrospective claims database study compared 2 FDC regimens, ARB/CCB and ACE inhibitor/CCB, in treating hypertensive patients with no known atherosclerotic cardiovascular disease. All patients were followed for at least 3 years or until the development of major adverse cardiovascular events (MACEs) during the study period. In addition, the effect of medication adherence on clinical outcomes was evaluated in subgroup analysis based on different portions of days covered.There was no significant difference in MACE-free survival (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.98–1.50; P = 0.08) and survival free from hospitalization for heart failure (HR: 1.15; 95% CI: 082–1.61; P = 0.431), new diagnosis of chronic kidney disease (HR: 0.98; 95% CI: 071–1.36; P = 0.906), and initiation of dialysis (HR: 0.99; 95% CI: 050–1.92; P = 0.965) between the 2 study groups. The results remained the same within each subgroup of patients with different adherence statuses.ARBs in FDC regimens with CCBs in the present study were shown to be as effective as ACE inhibitors at reducing the risks of MACEs, hospitalization for heart failure, new diagnosis of chronic kidney disease, and new initiation of dialysis in hypertensive patients, regardless of the medication adherence status.     

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Acute Coronary Syndrome: Implications for Platelet Reactivity?

Cardiovascular Drugs and Therapy - In patients with acute coronary syndrome (ACS), angiotensin-converting enzyme (ACE) inhibitors are preferred over angiotensin receptor blockers (ARBs). However,...     

Angiotensin Receptor Blockers and Tumorigenesis: Something To Be (or Not To Be) Concerned About?

The possibility of carcinogenic side effects of antihypertensive therapies due to their chronic administration has been raised multiple times in the past. Recently, the issue has again drawn attention, this time in relation to angiotensin receptor blockers (ARBs). This, among others, caused both American and European drug regulation authorities to review the underlying evidence concerning the relationship between this class of medications and potential adverse carcinogenic outcome. A plethora of both basic science and preclinical evidence has been generated, and three meta-analyses and one nationwide cohort have focused on this specific question. The current review aims to summarize the contemporary multidisciplinary evidence on whether ARBs may be associated with an increased risk of tumorigenesis.     

ACE Inhibitor‐Related Angioedema: Can Angiotensin‐Receptor Blockers Be Safely Used?

Angioedema is a well-recognized side effect of angiotensin-converting enzyme (ACE) inhibitor therapy. Angioedema can also be seen with angiotensin receptor blocker therapy but much less frequently than is the case with ACE inhibitors. For unclear reasons, ACE inhibitor-related angioedema occurs more commonly in black patients. Angioedema can be life threatening but more times than not its occurrence can be managed with conservative treatment measures including discontinuation of the medication and/or administration of an antihistamine. Occasionally, epinephrine and/or steroid therapy may be warranted. In a patient having experienced ACE inhibitor-related angioedema, angiotensin receptor blockers should be used cautiously if at all. If angiotensin receptor blocker therapy is being considered in a patient with prior ACE inhibitor-related angioedema there should be some justification for the use. Such justification might include the presence of heart failure or proteinuric nephropathic states among other considerations.     

Angiotensin‐Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers: Is There a Difference in Response and Any Advantage to Using Them Together in the Treatment of Hypertension?

In April 2008, a panel was convened to discuss the effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in the treatment of hypertension and the possible added benefit of using these agents together. The panel was moderated by Marvin Moser, MD, Clinical Professor of Medicine at Yale University School of Medicine, and included Clive Rosendorff, MD, PhD, Professor of Medicine at Mount Sinai School of Medicine and William B. White, MD, Division Chief, Hypertension and Clinical Pharmacology and Professor, Calhoun Cardiology Center at the University of Connecticut Health Center, Farmington.     

SPRINT and the Kidney: What Have We Learned?

Purpose of Review

To review the impact of the Systolic Blood Pressure Interventional Trial (SPRINT) on renal function and chronic kidney disease.

Recent Findings

Hypertension is a risk factor for cardiovascular and kidney outcomes in patients with chronic kidney disease (CKD). The benefits of intensive blood pressure lowering in the CKD population in previous studies are unclear. The SPRINT compared standard (<?140 mmHg) and intensive (<?120 mmHg) blood pressure management in nondiabetic patients with high risk of cardiovascular disease. In the subgroup of patients with CKD, the most important finding was that intensive blood pressure lowering is associated with lower risk of cardiovascular disease and mortality. Other than lower levels of albuminuria, there was no benefit on clinical kidney outcomes with the intensive treatment group. The risk of incident CKD and episodes of acute kidney injury was higher in patients in the intensive treatment group, though most patients with acute kidney injury recovered kidney function.

Summary

While the benefit of intensive blood pressure lowering on cardiovascular events and mortality with intensive blood pressure lowering is clear in patients with CKD, longer term follow-up may be needed to fully understand the effect on kidney function.

     

The Role of Stress and the Sympathetic Nervous System in Hypertension and Ischemic Heart Disease: Advantages of Therapy with β-Receptor Blockers

Human and animal studies link social and environmental factors to hypertension and ischemic heart disease. Job stress and undesirable life events may precede the development of raised blood pressure. Hypertension and ischemic heart disease vanquished many of the survivors of the seige of Leningrad.

Specific behavior patterns of some patients with ischemic heart disease and the pschological ambience of others with hypertension have been associated with raised neural tone as reflected by levels of plasma norepinephrine and epinephrine. Sympathoneural hypertonicity is a factor in left ventricular hypertrophy and the latter has been a prophet for sudden cardiac death. Sympathoadrenal surges may contribute to both reduced coronary reserve in hypertensives and increased vulnerabily to ventricular dysrhythmia.

The “coronary epidemic” of our modern times appears related in part to outdated survival mechanisms, not suitable to human behavior in our urban milieu. Beta receptor blocking agents are effective antidotes providing protection from adrenomedullary overdrive and even perhaps, modification of that behavior. Stress and the sympathetic nervous system are important co-conspirators in hypertension and sudden cardiac death.     

HDL and CETP Inhibition: Will This DEFINE the Future?

OPINION STATEMENT: The premature stopping of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) study due to futility has called into question the clinical value of high-density lipoprotein cholesterol (HDL-C) increases. The failure of estrogen therapy in the HERS (Heart and Estrogen/progestin Replacement Study) trial and the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib (in the ILLUMINATE [Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events] trial) and, most recently, dalcetrapib in the dal-OUTCOMES trial has cast doubt on the "HDL-raising hypothesis" for providing additional benefits on top of statin therapy. The AIM-HIGH trial was designed to equalize low-density lipoprotein cholesterol (LDL-C) levels between the two treatment groups while the niacin arm would have a higher HDL-C. The study population included patients with low HDL-C and cardiovascular disease (CVD); because this population has a high residual risk for CVD on statin therapy, these patients were most likely to benefit from the niacin HDL-C-raising effect. These findings are disappointing because clinicians have used extended-release niacin to treat patients with low HDL-C because niacin has demonstrated benefit in earlier reported studies in conjunction with statins and other drugs, as observed in the Cholesterol Lowering Atherosclerosis Study (CLAS) and the HDL-Atherosclerosis Treatment Study (HATS). In the Coronary Drug Project, niacin alone was shown to reduce myocardial infarction, stroke, and the need for coronary bypass surgery. Niacin does not increase the number of HDL particles to the same extent it raises HDL-C. Niacin alters the composition of HDL, making the particle larger, which is similar to the effects of CETP inhibition on HDL. Both niacin and CETP inhibitors decrease the catabolism of HDL, thereby increasing the size of the HDL particle and raising HDL-C. Dalcetrapib, which does not decrease LDL-C while raising HDL-C, was recently discontinued from clinical development due to a interim analysis that determined that the study was futile. Anacetrapib, which markedly increases HDL-C while also significantly lowering LDL-C, remains in clinical development, with a large cardiovascular end point trial currently enrolling 30,000 high-risk patients. For now, the goal remains the achievement of LDL-C and non-HDL targets, and low HDL-c remains a significant independent risk factor, but there is insufficient evidence that raising HDL-C will provide a clinical benefit.     

Hypertension and Kidney Disease: What Do the Data Really Show?

Hypertension is the most common co-morbidity in chronic kidney disease (CKD) and the optimal target BP to prevent CKD progression has been hotly debated. Prior recommendations by various groups for BP targets for CKD in the range of less than 130/80?mm Hg have been based on the assumed benefits of lower BP in this population with exceedingly high risk for cardiovascular disease (CVD). Although there is suggestive data that lower BP may be helpful in patients with proteinuria and CKD, studies not directly link a treatment-related reduction in proteinuria to a benefit in kidney outcomes. There are ongoing studies which will provide more data on BP targets in CKD. Based on the currently available data we recommend a BP goal of less than 140/90?mm Hg in all patients with CKD.