Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials

Objective To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination.Design Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, β blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose.Subjects 40 000 treated patients and 16 000 patients given placebo.Main outcome measures Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs.Results All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, β blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose.Conclusions Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.     

The Association of Cardioprotective Medications with Pneumonia-Related Outcomes

Introduction

Little research has examined whether cardiovascular medications, other than statins, are associated with improved outcomes after pneumonia. Our aim was to examine the association between the use of beta-blockers, statins, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) with pneumonia-related outcomes.

Materials and Methods

We conducted a retrospective population-based study on male patients ≥65 years of age hospitalized with pneumonia and who did not have pre-existing cardiac disease. Our primary analyses were multilevel regression models that examined the association between cardiovascular medication classes and either mortality or cardiovascular events.

Results

Our cohort included 21,985 patients: 22% died within 90 days of admission, and 22% had a cardiac event within 90 days. The cardiovascular medications studied that were associated with decreased 90-day mortality included: statins (OR 0.70, 95% CI 0.63–0.77), ACE inhibitors (OR 0.82, 95% CI 0.74–0.91), and ARBs (OR 0.58, 95% CI 0.44–0.77). However, none of the medications were significantly associated with decreased cardiovascular events.

Discussion

While statins, ACE inhibitors, and ARBs, were associated with decreased mortality, there was no significant association with decreased CV events. These results indicate that this decreased mortality is unlikely due to their potential cardioprotective effects.     

Impact of statins and ACE inhibitors on mortality after COPD exacerbations

Background

The purpose of our study was to examine the association of prior outpatient use of statins and angiotensin converting enzyme (ACE) inhibitors on mortality for subjects ≥ 65 years of age hospitalized with acute COPD exacerbations.

Methods

We conducted a retrospective national cohort study using Veterans Affairs administrative data including subjects ≥65 years of age hospitalized with a COPD exacerbation. Our primary analysis was a multilevel model with the dependent variable of 90-day mortality and hospital as a random effect, controlling for preexisting comorbid conditions, demographics, and other medications prescribed.

Results

We identified 11,212 subjects with a mean age of 74.0 years, 98% were male, and 12.4% of subjects died within 90-days of hospital presentation. In this cohort, 20.3% of subjects were using statins, 32.0% were using ACE inhibitors or angiotensin II receptor blockers (ARB). After adjusting for potential confounders, current statin use (odds ratio 0.51, 95% confidence interval 0.40–0.64) and ACE inhibitor/ARB use (0.55, 0.46–0.66) were significantly associated with decreased 90-day mortality.

Conclusion

Use of statins and ACE inhibitors prior to admission is associated with decreased mortality in subjects hospitalized with a COPD exacerbation. Randomized controlled trials are needed to examine whether the use of these medications are protective for those patients with COPD exacerbations.     

A strategy to reduce cardiovascular disease by more than 80%

Objectives To determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels.Design We quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta-analysis of 15 trials of low dose (50-125 mg/day) aspirin.Outcome measures Proportional reduction in ischaemic heart disease (IHD) events and strokes; life years gained; and prevalence of adverse effects.Results The formulation which met our objectives was: a statin (for example, atorvastatin (daily dose 10 mg) or simvastatin (40 mg)); three blood pressure lowering drugs (for example, a thiazide, a β blocker, and an angiotensin converting enzyme inhibitor), each at half standard dose; folic acid (0.8 mg); and aspirin (75 mg). We estimate that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%). One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke. Summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation).Conclusion The Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention.     

Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories

Objective To describe characteristics of dosing history in patients prescribed a once a day antihypertensive medication.Design Longitudinal database study.Setting Clinical studies archived in database for 1989-2006.Participants Patients who participated in the studies whose dosing histories were available through electronic monitoring.Main outcome measures Persistence with prescribed antihypertensive treatment and execution of their once a day drug dosing regimens.Results The database contained dosing histories of 4783 patients with hypertension. The data came from 21 phase IV clinical studies, with lengths ranging from 30 to 330 days and involving 43 different antihypertensive drugs, including angiotensin II receptor blockers (n=2088), calcium channel blockers (n=937), angiotensin converting enzyme inhibitors (n=665), β blockers (n=195), and diuretics (n=155). About half of the patients who were prescribed an antihypertensive drug had stopped taking it within one year. On any day, patients who were still engaged with the drug dosing regimen omitted about 10% of the scheduled doses: 42% of these omissions were of a single day’s dose, whereas 43% were part of a sequence of several days (three or more days—that is, drug “holidays”). Almost half of the patients had at least one drug holiday a year. The likelihood that a patient would discontinue treatment early was inversely related to the quality of his or her daily execution of the dosing regimen.Conclusions Early discontinuation of treatment and suboptimal daily execution of the prescribed regimens are the most common facets of poor adherence with once a day antihypertensive drug treatments. The shortfalls in drug exposure that these dosing errors create might be a common cause of low rates of blood pressure control and high variability in responses to prescribed antihypertensive drugs.     

Platelet Expression of Stromal Cell-Derived Factor-1 Is Associated with the Degree of Valvular Aortic Stenosis

Background and Purpose

Platelet surface expression of stromal-cell-derived factor-1 (SDF-1) is increased during platelet activation and constitutes an important factor in hematopoetic progenitor cell trafficking at sites of vascular injury and ischemia. Enhanced platelet SDF-1 expression has been reported previously in patients suffering from acute coronary syndrome (ACS). We hypothesized that expression of platelet associated SDF-1 may also be influenced by calcified valvular aortic stenosis (AS).

Methods

We consecutively evaluated 941 patients, who were admitted to the emergency department with dyspnea and chest pain. Platelet surface expression of SDF-1 was determined by flow cytometry, AS was assessed using echocardiography and hemodynamic assessment by heart catheterization. A 1∶1 propensity score matching was implemented to match 218 cases with 109 pairs adjusting for age, sex, cardiovascular risk factors, and medication including ACE inhibitors, angiotensin receptor blockers, beta blockers, statins, aspirin, clopidogrel, GPIIb/IIIa antagonists, and vitamin K antagonists.

Results

Patients with valvular AS showed enhanced platelet SDF-1 expression compared to patients without AS (non-valvular disease, NV) independent of ACS and stable coronary artery disease (SAP) [mean fluorescence intensity (MFI) for ACS (AS vs. NV): 75±40.4 vs. 39.5±23.3; P = 0.002; for SAP (AS vs. NV): 54.9±44.6 vs. 24.3±11.2; P = 0.008]. Moreover, the degree of AS significantly correlated with SDF-1 platelet surface expression (r = 0.462; P = 0.002).

Conclusions

Valvular AS is associated with enhanced platelet-SDF-1 expression; moreover the degree of valvular AS correlates with SDF-1 platelet surface expression. These findings may have clinical implications in the future.     

Factors associated with the use of evidence-based therapies after discharge among elderly patients with myocardial infarction

Background

In an accompanying article, we report moderate between-hospital variation in the postdischarge use of β-blockers, angiotensin-modifying drugs and statins by elderly patients who had been admitted to hospital with acute myocardial infarction. Our objective was to identify the characteristics of patients, physicians, hospitals and communities associated with differences in the use of these medications after discharge.

Methods

For this retrospective, population-based cohort study, we used linked administrative databases. We examined data for all patients aged 65 years or older who were discharged from hospital in 2005/06 with a diagnosis of myocardial infarction. We determined the effect of patient, physician, hospital and community characteristics on the rate of postdischarge medication use.

Results

Increasing patient age was associated with lower postdischarge use of medications. The odds ratios (ORs) for a 1-year increase in age were 0.98 (95% confidence interval [CI] 0.97–0.99) for β-blockers, 0.97 (95% CI 0.97–0.98) for angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers and 0.94 (95% CI 0.93–0.95) for statins. Having a general or family practitioner, a general internist or a physician of another specialty as the attending physician, relative to having a cardiologist, was associated with lower postdischarge use of β-blockers, angiotensin-modifying agents and statins (ORs ranging from 0.46 to 0.82). Having an attending physician with 29 or more years experience, relative to having a physician who had graduated within the past 15 years, was associated with lower use of β-blockers (OR 0.71, 95% CI 0.60–0.84) and statins (OR 0.81, 95% CI 0.67–0.97).

Interpretation

Patients who received care from noncardiologists and physicians with at least 29 years of experience had substantially lower use of evidence-based drug therapies after discharge. Dissemination strategies should be devised to improve the prescribing of evidence-based medications by these physicians.The use of medications such as acetylsalicylic acid (ASA), β-blockers, angiotensin-modifying drugs (angiotensin-converting-enzyme [ACE] inhibitors and angiotensin-receptor blockers) and statins is a mainstay of secondary prevention of myocardial infarction. In a companion study published in this issue of CMAJ, we report substantial increases in the use of evidence-based drug therapies after discharge among elderly patients with myocardial infarction over a 14-year period.¹ However, despite temporal improvements, the prescribing of evidence-based drug therapies differed among hospitals in 2005.Studies from the late 1980s to the mid-1990s showed that the prescribing of evidence-based drug therapies was influenced by patient characteristics.^2–6 However, the extent to which postdischarge prescribing is influenced by patient, physician, hospital and community characteristics has not been extensively explored.Our objective was to identify patient, physician, hospital and community characteristics associated with the use of of evidence-based drug therapies after discharge among patients with myocardial infarction.     

Cardiovascular and Renal Outcomes of Renin–Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses

Background

Medications aimed at inhibiting the renin–angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes.

Methods and Findings

Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke—singly and as a composite endpoint, major cardiovascular outcome—and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality—singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90–1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79–1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96–1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73–1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90–1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72–1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65–1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78–1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints.

Conclusions

In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment.

Review registration

PROSPERO CRD42014014404     

Cardiac Overexpression of Constitutively Active Galpha q Causes Angiotensin II Type1 Receptor Activation,Leading to Progressive Heart Failure and Ventricular Arrhythmias in Transgenic Mice

Background

Transgenic mice with transient cardiac expression of constitutively active Galpha q (Gα_q-TG) exhibt progressive heart failure and ventricular arrhythmias after the initiating stimulus of transfected constitutively active Gα_q becomes undetectable. However, the mechanisms are still unknown. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in Gα_q-TG mice.

Methodology/Principal Findings

Olmesartan (1 mg/kg/day) or vehicle was chronically administered to Gα_q-TG from 6 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic olmesartan administration prevented the severe reduction of left ventricular fractional shortening, and inhibited ventricular interstitial fibrosis and ventricular myocyte hypertrophy in Gα_q-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated Gα_q-TG but in none of 10 olmesartan-treated Gα_q-TG. The collected QT interval and monophasic action potential duration in the left ventricle were significantly shorter in olmesartan-treated Gα_q-TG than in vehicle-treated Gα_q-TG. CTGF, collagen type 1, ANP, BNP, and β-MHC gene expression was increased and olmesartan significantly decreased the expression of these genes in Gα_q-TG mouse ventricles. The expression of canonical transient receptor potential (TRPC) 3 and 6 channel and angiotensin converting enzyme (ACE) proteins but not angiotensin II type 1 (AT₁) receptor was increased in Gα_q-TG ventricles compared with NTG mouse ventricles. Olmesartan significantly decreased TRPC6 and tended to decrease ACE expressions in Gα_q-TG. Moreover, it increased AT₁ receptor in Gα_q-TG.

Conclusions/Significance

These findings suggest that angiotensin II type 1 receptor activation plays an important role in the development of heart failure and ventricular arrhythmia in Gα_q-TG mouse model of heart failure.     

Dyspnoea,asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE--To evaluate the occurrence of asthma and dyspnoea precipitated or worsened by angiotensin converting enzyme inhibitors. DESIGN--Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisation''s international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised. SUBJECTS--Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions. MAIN OUTCOME MEASURES--Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea. RESULTS--In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had adverse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dyspnoea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors. CONCLUSION--Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.     

Metabolic modulation and cellular therapy of cardiac dysfunction and failure

At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy. Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy.     

Statins Promote the Degradation of Extracellular Amyloid β-Peptide by Microglia via Stimulation of Exosome-associated Insulin-degrading Enzyme (IDE) Secretion

Epidemiological studies indicate that intake of statins decrease the risk of developing Alzheimer disease. Cellular and in vivo studies suggested that statins might decrease the generation of the amyloid β-peptide (Aβ) from the β-amyloid precursor protein. Here, we show that statins potently stimulate the degradation of extracellular Aβ by microglia. The statin-dependent clearance of extracellular Aβ is mainly exerted by insulin-degrading enzyme (IDE) that is secreted in a nonconventional pathway in association with exosomes. Stimulated IDE secretion and Aβ degradation were also observed in blood of mice upon peripheral treatment with lovastatin. Importantly, increased IDE secretion upon lovastatin treatment was dependent on protein isoprenylation and up-regulation of exosome secretion by fusion of multivesicular bodies with the plasma membrane. These data demonstrate a novel pathway for the nonconventional secretion of IDE via exosomes. The modulation of this pathway could provide a new strategy to enhance the extracellular clearance of Aβ.     

Heart failure and angiotensin converting enzyme inhibition: problems and perspectives.

Heart failure has become the most widely studied syndrome in cardiology over the recent years. Despite the encouraging achievements by angiotensin converting enzyme (ACE) inhibitors, the mortality of patients with chronic heart failure remains high. There are several factors which can potentially be responsible for the fact that about 80% of patients with a failing heart defy protection by ACE inhibitors: different activation of tissue and systemic renin-angiotensin system (RAS) in a particular heart disease and the distinct ability of various ACE inhibitors to block cardiac ACE, alternative pathways for angiotensin II formation (chymase), genetic polymorphism of the RAS system and the complexity of neuroendocrine activation. Moreover, chronic heart failure can provoke disturbances in the reactivity of peripheral vessels and metabolism of striated muscles. These factors may then potentiate the vicious circle of heart failure. New therapeutic approaches, which could further reduce the mortality in patients with heart failure involve angiotensin II type 1 receptor antagonists, beta-blockers, aldosterone antagonists and blockers of the endothelin receptor. A number of questions associated with functions of the RAS still remain open and their solution could be of substantial benefit for patients with a failing heart.     

Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE--To evaluate and describe the clinical course of angio-oedema reactions induced by angiotensin converting enzyme inhibitors. DESIGN AND METHODS--All reports of angio-oedema reactions associated with angiotensin converting enzyme inhibitors submitted to Swedish Adverse Reactions Advisory Committee were reviewed and the clinical courses summarised. Numbers of cases judged to be induced by angiotensin converting enzyme inhibitors were related to their annual usage, estimated from total sales of defined daily doses, as well as to the estimated number of new patients. All cases of angio-oedema associated with angiotensin converting enzyme inhibitors reported to the World Health Organisation''s international drug information system were also summarised. RESULTS--36 of the 38 reported cases in Sweden between 1981 and 1990 were judged to be related to angiotensin converting enzyme inhibitors. During 1981 through 1990, altogether 1309 cases of angio-oedema associated with angiotensin converting enzyme inhibitors were registered with the international drug information system. The incidence of reported cases of angio-oedema increased largely in parallel with the increased sales (usage) of angiotensin converting enzyme inhibitors. Of the 36 Swedish patients, 77% experienced the reaction within the first three weeks after starting treatment. 10 patients needed hospitalisation, two of whom had life threatening laryngeal obstruction. With one exception all 36 patients were free of symptoms within one week after discontinuing the drug. CONCLUSIONS--Angio-oedema induced by angiotensin converting enzyme inhibitors is a rare but potentially life threatening reaction, which in most instances occurs shortly after the start of treatment. Any patient in whom the reaction is suspected should have the treatment interrupted and, if necessary, be admitted for observation.     

Controlling oxidative stress as a novel molecular approach to protecting the vascular wall in diabetes

PURPOSE OF REVIEW: In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications; therefore an antioxidant therapy would be of great interest in this disease. RECENT FINDINGS: Hyperglycemia directly promotes an endothelial dysfunction--inducing process of overproduction of superoxide at the mitochondrial level. This is the first and key event able to activate all the pathways involved in the development of vascular complications of diabetes. It has recently been shown that statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 blockers, calcium channel blockers, and thiazolidinediones have a strong intracellular antioxidant activity. SUMMARY: Classic antioxidants, such as vitamin E, failed to show beneficial effects on diabetic complications probably because their action is only "symptomatic". The preventive activity against hyperglycemia-induced oxidative stress shown by statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 blockers, calcium channel blockers, and thiazolidinediones justifies use of these compounds for preventing complications in patients with diabetes, in whom antioxidant defences have been shown to be defective.     

Comparative effectiveness of angiotensin-receptor blockers for preventing macrovascular disease in patients with diabetes: a population-based cohort study

Background:

Telmisartan, unlike other angiotensin-receptor blockers, is a partial agonist of peroxisome proliferator–activated receptor-γ, a property that has been associated with improvements in surrogate markers of cardiovascular health in small trials involving patients with diabetes. However, whether this property translates into a reduced risk of cardiovascular events and death in these patients is unknown. We sought to explore the risk of myocardial infarction, stroke and heart failure in patients with diabetes who were taking telmisartan relative to the risk of these events occurring in patients taking other angiotensin-receptor blockers.

Methods:

We conducted a population-based, retrospective cohort study of Ontario residents with diabetes aged 66 years and older who started treatment with candesartan, irbesartan, losartan, telmisartan or valsartan between Apr. 1, 2001, and Mar. 31, 2011. Our primary outcome was a composite of admission to hospital for acute myocardial infarction, stroke or heart failure. We examined each outcome individually in secondary analyses, in addition to all-cause mortality.

Results:

We identified 54 186 patients with diabetes who started taking an angiotensin-receptor blocker during the study period. After multivariable adjustment, patients who took either telmisartan (adjusted hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.74–0.97) or valsartan (adjusted HR 0.86, 95% CI 0.77–0.95) had a lower risk of the composite outcome compared with patients who took irbesartan. In contrast, no significant difference in risk was seen between other angiotensin-receptor blockers and irbesartan. In secondary analyses, we found a reduced risk of admission to hospital for heart failure with telmisartan compared with irbesartan (adjusted HR 0.79, 95% CI 0.66–0.96), but no significant differences in risk were seen between angiotensin-receptor blockers in our other secondary analyses.

Interpretation:

Compared with other angiotensin-receptor blockers, telmisartan and valsartan were both associated with a lower risk of admission to hospital for acute myocardial infarction, stroke or heart failure among older adults with diabetes and hypertension. Telmisartan and valsartan may therefore be the preferred angiotensin-receptor blockers for use in these patients.About 366 million people worldwide live with diabetes, a number that is projected to increase to 552 million by 2030.¹ Because disease-attributable macrovascular complications are the principal causes of death for people with type 2 diabetes, many therapies have the goal of reducing vascular events among these patients.^2,3 Blockade of the renin–angiotensin–aldosterone system with angiotensin-receptor blockers is a commonly used and particularly appealing strategy in this regard, given the multiple mechanisms through which angiotensin II contributes to a heightened risk of diabetes-related macrovascular disease and the superior tolerability profile of these drugs relative to angiotensin-converting enzyme (ACE) inhibitors.^4–6Although angiotensin-receptor blockers are considered largely interchangeable in clinical practice, evidence from experimental studies and small comparative trials suggest that telmisartan exhibits several pleoiotropic properties that distinguish it from other members of this drug class.⁷ Most notably, telmisartan is a partial agonist of peroxisome proliferator–activated receptor-γ (PPARγ), a property associated with improvements in surrogate markers of cardiovascular health in small trials involving patients with type 2 diabetes.^8–13 However, whether telmisartan-mediated activation of PPARγ is associated with a reduced risk of macrovascular events in patients with diabetes relative to angiotensin-receptor blockers that do not share this property is unknown.We sought to compare the risk of acute myocardial infarction, heart failure and stroke in older patients whose diabetes was also managed with either telmisartan or any of candesartan, irbesartan, losartan and valsartan. We speculated that, owing to its pleiotropic effects, telmisartan would be associated with a lower risk of macrovascular events in these patients relative to other angiotensin-receptor blockers.     

Changing patterns in drug therapy for ischemic heart disease

To determine the possible influence of studies on β-blocker therapy following myocardial infarction and the introduction of calcium-channel blockers on the prescribing habits of physicians in a large urban centre, the drug therapy received by 100 patients with ischemic heart disease (IHD) (50 with myocardial infarction and 50 with unstable angina) admitted to a university teaching hospital in 1980 was compared with that received by another such group of 100 patients admitted in 1983-84. The proportion of patients with myocardial infarction receiving drug therapy was significantly higher in 1983-84, at the time of both admission (p < 0.01) and discharge (p < 0.001). Much of the increase was due to greater use of β-blockers. Of the 50 patients with unstable angina in 1983-84, 20 were taking calcium-channel blockers when admitted, and 29 were taking them when discharged. In both 1980 and 1983-84 unstable angina was treated more vigorously than myocardial infarction. The results suggest that physicians have developed a more aggressive approach to drug therapy for IHD since the publication of the β-blocker studies and the introduction of calcium-channel blockers.     

Inhibition of Renin Angiotensin Axis May Be Associated with Reduced Risk of Developing Venous Thromboembolism in Patients with Atherosclerotic Disease

Background

Arterial and venous thrombosis may share common pathophysiology involving the activation of platelets and inflammatory mediators. A growing body of evidence suggests prothrombotic effect of renin angiotensin system (RAS) including vascular inflammation and platelet activation. We hypothesized that the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) plays a role in protecting against venous thromboembolism (VTE) in patients atherosclerosis.

Methods

We conducted a retrospective study, reviewing 1,100 consecutive patients admitted to a teaching hospital with a diagnosis of either myocardial infarction or ischemic stroke from 2005 to 2010. Patients who had been treated with anticoagulation therapy before or after the first visit were excluded. The occurrence of VTE during the follow up period, risk factors for VTE on admission, and the use of ACEIs or ARBs during the follow up period were recorded.

Results

The mean age of the entire study population was 68.1 years. 52.0% of the patients were female and 76.5% were African American. 67.3% were on RAS inhibitorsThe overall incidence of VTE was 9.7% (n = 107). Among the RAS inhibitor users, the incidence of VTE events was 9.0% (54/603) for the ACEI only users, 7.1% (8/113) for the ARB only users, and 0% (0/24) for the patients taking combination of ACEI and ARB. Among patients on RAS inhibitors, 8.4% (62/740) developed a VTE, compared with 12.5% (45/360) in the nonuser group [HR (hazard ratio), 0.58; 95% CI (confidence interval), 0.39–0.84; P<0.01]. Even after controlling for factors related to VTE (smoking, history of cancer, and immobilization, hormone use) and diabetes, the use of RAS inhibitors was still associated with a significantly lower risk of developing VTE (AHR, 0.59; 95% CI, 0.40–0.88; P = 0.01).

Conclusions

The use of RAS inhibitors appears to be associated with a reduction in the risk of VTE.     

Peripheral blood mononuclear cell microRNAs in coronary artery disease

The accuracy of risk prediction for coronary artery disease can be improved with the use of novel molecular or genetic biomarkers. In this study, we investigated the difference of five selected microRNAs (miR or miRNA) in patients with coronary artery disease (CAD) and controls, assessed by coronary angiography. The study population consisted of 85 subjects, aged between 18 and 75 years and underwent invasive coronary angiography. Subjects with more than 30% stenosis in at least one coronary artery, patients with a history of prior percutaneous coronary intervention or coronary by-pass surgery were allocated to the patient group; whereas the subjects without at least 30% stenosis consisted the control group. Groups were similar in age, presence of hypertension, and smoking status. However, the proportion of males and subjects taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, nitrates, and statins were higher in the patient group. miR-221 and miR-155 were downregulated (P = .02 and .001, respectively), while miR-21 levels were significantly increased (P = .003) in the patient group compared to controls. Changes in miR-145 and miR-126 did not reach statistical significance (P > .05). miRNA- 21, miR-155, and miR-221 were differentially expressed between the patients and controls. miRNAs are promising biomarkers for CAD diagnosis, however, this requires further research with larger groups.