Effect of cardiovascular drug classes on all-cause mortality among atrial fibrillation patients treated in primary care in Sweden: a cohort study

Background

Risk factors for stroke are well known in atrial fibrillation (AF) patients, while less is known on the effect of these factors on total mortality.

Objective

Our aim was to study the impact of cardiovascular drug classes on mortality in AF patients treated in primary care.

Methods

The study population was chosen based on patient data from 75 primary care centres in Sweden compiled in a database. Individuals diagnosed with AF who were older than 45 years were enrolled (n?=?12,302, of whom?6,660 were men). Cox regression analysis with mortality (years to death) as outcome was conducted in the men and women separately, as well in the age categories <80 and ≥80 years, with cardiovascular drugs as independent factors, and age, cardiovascular diagnoses and educational level as covariates.

Results

Lower mortality was shown for anticoagulant treatment among men, both younger (<80 years) [adjusted hazard ratio (HR) 0.43, 95 % confidence interval (CI) 0.31–0.61] and older (≥80 years) (adjusted HR 0.47, 95 % CI 0.32–0.69), and among younger women (adjusted HR 0.46, 95 % CI 0.29–0.74), and for antiplatelet treatment in older men (adjusted HR 0.51, 95 % CI 0.35–0.74). Treatment with thiazides was associated with lower mortality among younger men (adjusted HR 0.68, 95 % CI 0.48–0.96), older men (adjusted HR 0.67, 95 % CI 0.46–0.98) and older women (adjusted HR 0.70, 95 % CI 0.52–0.94). Statins were associated with lower mortality among younger patients, in both men (adjusted HR 0.47, 95 % CI 0.32–0.68) and women (adjusted HR 0.54, 95 % CI 0.35–0.82).

Conclusions

The differences in age and gender patterns need further exploration.     

Association between spironolactone added to beta-blockers and ACE inhibition and survival in heart failure patients with reduced ejection fraction: a propensity score-matched cohort study

Purpose

Heart failure (CHF) guidelines recommend mineralocorticoid receptor antagonists for all symptomatic patients treated with a combination of ACE inhibitors/angiotensin receptor blockers (ARBs) and beta-blockers. As opposed to both eplerenone trials, patients in RALES (spironolactone) received almost no beta-blockers. Since pharmacological properties differ between eplerenone and spironolactone, the prognostic benefit of spironolactone added to this baseline combination therapy needs clarification.

Methods

We included 4,832 CHF patients with chronic systolic dysfunction from the Norwegian Heart Failure Registry and the heart failure outpatients’ clinic of the University of Heidelberg. Propensity scores for spironolactone receipt were calculated for each patient and used for matching to patients without spironolactone.

Results

During a total follow-up of 17,869 patient-years, 881 patients (27.0 %) died in the non-spironolactone group and 445 (28.4 %) in the spironolactone group. Spironolactone was not associated with improved survival, neither in the complete sample (HR 0.82; 95 % CI 0.64–1.07; HR 1.03; 95 % CI 0.88–1.20; multivariate and propensity score adjusted respectively), nor in the propensity-matched cohort (HR 0.98; 95 % CI 0.82–1.18).

Conclusion

In CHF outpatients we were unable to observe an association between the use of spironolactone and improved survival when administered in addition to a combination of ACE/ARB and beta-blockers.     

Cardiovascular Outcomes in High-Risk Patients without Heart Failure Treated with ARBs

Background and objective

Angiotensin II type 1 receptor antagonists (ARBs) are widely used as a substitute for angiotensin-converting enzyme inhibitors (ACEIs) to treat patients without heart failure, but their effect on cardiovascular morbidity and mortality has not been clearly determined. A systematic review and metaanalysis was undertaken to determine the impact of ARBs on cardiovascular outcomes in high-risk patients without heart failure.

Methods

A computerized literature search was carried out using PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, and EMBASE, from January 1990 to April 2008. The following search terms were used: ‘hypertension’, ‘clinical trial’, ‘sartan’, ‘ARB’, ‘angiotensin receptor antagonist’, ‘losartan’, ‘candesartan’, ‘valsartan’, ‘irbesartan’, ‘eprosartan’, ‘telmisartan’, ‘olmesartan’, ‘coronary disease’, ‘coronary heart disease’, ‘myocardial infarction’, ‘cardiovascular disease’, ‘cerebrovascular disease’, and ‘stroke’. Criteria for inclusion of clinical trials in our meta-analysis were the use of a randomized control group not receiving an ARB and the availability of outcome data for any one of four endpoints: myocardial infarction (MI), stroke, cardiovascular death, and all-cause death (these were not always pre-specified endpoints in all trials). Out of 45 potentially relevant studies, 37 trials met the inclusion criteria. We tabulated all occurrences of these four adverse outcomes.

Results

Homogenous subgroups were combined by means of a fixed-effects model, while heterogenous subgroups were not combined. In the subgroup without heart failure, ARBs, when compared with the control group, had an odds ratio of 1.09 (95% CI 1.00, 1.18; p = 0.05) for MI. Other endpoints, namely, cardiovascular death and all-cause death, did not reach statistical significance. There was a clear trend for fewer strokes in the ARB group, but these studies were clearly heterogenous, and therefore a pooled risk estimate was not computed.

Conclusion

After pooling more than 89 000 patients, there is no evidence to suggest that ARBs confer cardiovascular protection akin to ACEIs, and the results that emerged are not in favor of ARB therapy in terms of its use as a substitute for ACEIs in non-heart failure patients. ARBs may have a small benefit in terms of stroke risk, but the studies are heterogenous, making it very difficult to quantify this effect. Given that ACEIs protect against both stroke and MI, caution is advised in the use of ARBs as a substitute for ACEIs in patients without a heart failure indication, who are tolerant of an ACEI.     

Incidence of and Risk Factors for Severe Adverse Events in Elderly Patients Taking Angiotensin‐Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers after an Acute Myocardial Infarction

Study Objective

To assess the incidence of and risk factors associated with severe adverse events in elderly patients who used angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) after an acute myocardial infarction (AMI).

Design

Retrospective cohort study.

Data Sources

Centers for Medicare & Medicaid Services Chronic Conditions Data Warehouse (Medicare service claims database), American Community Survey of the U.S. Census Bureau, and Multum Lexicon Drug database.

Patients

A total of 101,588 eligible Medicare fee‐for‐service beneficiaries 66 years or older, who were hospitalized for AMI between January 1, 2008, and December 31, 2009, and used ACEIs or ARBs within 30 days after discharge.

Measurements and Main Results

Primary outcomes were hospitalizations for acute renal failure (ARF) and hyperkalemia. The secondary outcome was discontinuation or suspension of ACEI/ARB therapy after a visit to a health care provider. The primary risk factors of interest were age, sex, race/ethnicity, and chronic kidney disease (CKD). Cumulative incidence curves and multivariable Fine‐Gray proportional hazards models with 95% confidence intervals (CIs) were used with death as a competing risk in both intention‐to‐treat (ITT) and as‐treated (AT) analyses. In the study cohort, 2.8% experienced ARF, 0.5% experienced hyperkalemia, and 63.7% discontinued ACEI/ARB therapy within 1 year after hospital discharge. Approximately half of the incidence of ARF and hyperkalemia occurred within 6 months after hospital discharge, but the cumulative incidence increased after 6 months. Patients older than 85 years had a higher rate of ARF (ITT hazard ratio [HR] 1.15, 95% CI 1.04–1.28) and hyperkalemia (ITT HR 1.33, 95% CI 1.05–1.68) compared with those aged 65–74 years. Patients with baseline CKD had higher rates of ARF (ITT HR 1.61, 95% CI 1.42–1.82), hyperkalemia (ITT HR 1.41, 95% CI 1.11–1.77), and ACEI/ARB therapy discontinuation or suspension (ITT HR 1.05, 95% CI 1.02–1.09).

Conclusion

We found a low incidence of ARF and hyperkalemia in elderly patients treated with ACEIs or ARBs after AMI hospitalization. However, a high rate of treatment discontinuation might prevent a higher rate of occurrence of these events. Long‐term careful monitoring of severe adverse events and timely discontinuation of ACEIs or ARBs among elderly patients with advancing age and CKD after an AMI is warranted in clinical practice.     

Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors or chemotherapy alone in advanced NSCLC: a meta-analysis of randomized controlled trials

Background

Most patients with advanced non-small-cell lung cancer (NSCLC) require systemic chemotherapy. Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors (TKI; e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, axitinib) has recently been evaluated in patients with NSCLC. However, the advantage of this therapy over chemotherapy alone in patients with advanced NSCLC remains largely unknown.

Methods

A meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy and toxicity of chemotherapy plus multitargeted antiangiogenic TKI with chemotherapy alone in patients with advanced NSCLC. PubMed, the ASCO and ESMO databases, and the Cochrane Library were searched for references to published articles. Two reviewers independently assessed the quality of the trials. Data were extracted, and overall response rate (ORR), pooled progression-free survival (PFS), overall survival (OS) with 95 % confidence intervals (CI), and major toxicities/adverse effects were analyzed.

Results

Six RCTs involving 3,337 patients with advanced NSCLC were ultimately analyzed. Compared to chemotherapy alone, chemotherapy plus multitargeted antiangiogenic TKI significantly increased the ORR [relative risk (RR)?1.71, 95 % CI??1.43–2.05] and PFS [hazard ratio (HR) ?0.83, 95 % CI?0.76–0.90], but not OS (HR 0.93, 95 % CI?0.83–1.03). Patients who received chemotherapy plus multitargeted antiangiogenic TKI exhibited more rash, diarrhea and hypertension (OR?2.78, 95 % CI? 2.37–3.26; OR?1.92, 95 % CI?1.65–2.24; OR ?2.90, 95 % CI?2.19–3.84, respectively) and less nausea and vomiting (OR?0.71, 95 % CI?0.60–0.83; OR?0.75, 95 % CI?0.61–0.92, respectively). The incidence of hemorrhage, fatigue, cough, constipation, anorexia, and alopecia were comparable between the two groups.

Conclusions

Therapy consisting of chemotherapy plus multitargeted antiangiogenic TKI was found to have specific advantages over chemotherapy alone in terms of PFS and ORR. The toxicity was comparable between the two therapies. Therefore, chemotherapy plus multitargeted antiangiogenic TKI may be a safe and valid therapeutic option for patients with advanced NSCLC.     

Non-steroidal anti-inflammatory drug use in chronic pain conditions with special emphasis on the elderly and patients with relevant comorbidities: management and mitigation of risks and adverse effects

Purpose

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs, and this widespread use is complicated by safety issues.

Method

A Literature review was conducted.

Results

NSAIDs are a leading cause of drug-related morbidity, especially in the elderly and patients with comorbidities. Most adverse effects are related to generalized inhibition of the major targets of NSAIDs: cyclooxygenases I and II. These enzymes are not only involved in pain and inflammation pathogenesis but are also required in the gastrointestinal (GI) tract for mucosal protection and gut motility, and in the kidneys for functional integrity. Thus, the mechanisms of NSAID toxicity are well understood, but the consequences are largely uncontrolled in clinical practice. GI ulcers, including bleeding ulcers, may occur in several percent of all chronic unprotected, high-dose NSAID users. Renal side effects may precipitate renal failure, resulting in acute dialysis and chronic retention. This includes sodium retention, resulting in arterial hypertension, heart failure, and atherosclerotic events. Cardiovascular risk may be tripled by chronic high-dose NSAID use in long-term clinical trials though “real-life studies” indicate lower risk ratios. Off-target side effects include allergic reactions, drug-induced liver injury, and central nervous system effects.

Conclusions

Management of pain and inflammation must consider those risks and find alternative drugs or approaches to limit the negative impact of NSAIDs on mortality and morbidity. Alternative drugs, low-dose/short-term use, but especially non-pharmacologic approaches, such as physiotherapy, exercise, neurophysiologic measures, and local therapies, need to be further utilized. The appalling equation “less pain–more deaths/morbidity” ultimately necessitates treatment optimization in the individual patient.     

Neointimal Hyperplasia Inhibition Effect of Angiotensin II Type 1 Receptor Blockers in Patients after Coronary Stent Implantation

Background and Objective

It remains unclear whether angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) can inhibit neointimal hyperplasia after stent implantation in patients with coronary artery disease. The aim of this meta-analysis was therefore to evaluate the benefits of ARBs in patients after coronary stent implantation based on the currently available randomized controlled trials.

Methods

We conducted a pooled analysis of randomized controlled trials to compare outcomes after stent implantation in patients administered ARBs with those not administered ARBs. We searched Ovid/MEDLINE, EMBASE, and the ISI web of knowledge using the terms ‘angiotensin receptor blocker,’ ‘renin angiotensin system inhibitor,’ ‘angiotensin receptor antagonist,’ ‘stent,’ ‘angiograph,’ ‘percutaneous coronary intervention (PCI),’ and ‘coronary artery disease.’ Published meta-analyses, review articles, and editorials were reviewed for potential studies of interest. The inclusion criteria were randomized controlled trials published in English, with a follow-up period of 6 months, comparing the outcomes after coronary stent implantation with and without the administration of any kind of ARB, reporting at least one outcome of interest (restenosis rate and late lumen loss). Data abstraction included study design, patient characteristics, follow-up period, type of ARB, type of stent, restenosis rate, and late lumen loss. Fixed-effects models were used to calculate the pooled relative risk for the restenosis rate and the standardized mean difference for late lumen loss.

Results

Five studies were included, with a total number of 624 patients. Seventy-five of 314 patients in the ARB group were diagnosed with in-stent restenosis at the 6-month follow-up, compared with 87 of 310 patients in the control group (relative risk 0.85; 95% CI 0.65, 1.11; p = 0.23). Consistent with this, there was no significant difference in late lumen loss between the two groups (0.04 mm; 95% CI ?0.15, 0.23; p = 0.66).

Conclusion

There is no evident benefit with the use of an ARB in terms of inhibition of neointimal hyperplasia in patients after coronary stent implantation.     

Association of long-term adherence to evidence-based combination drug therapy after acute myocardial infarction with all-cause mortality. A prospective cohort study based on claims data

Purpose

To determine long-term adherence to evidence-based secondary preventive combination pharmacotherapy in survivors of acute myocardial infarction (AMI) and to investigate the association between adherence to recommended therapy and all-cause mortality in claims data.

Methods

Prospective cohort study based on claims data of an 18.75?% random sample of all persons insured with the local statutory health insurance fund AOK Hesse. Study population included patients with hospital discharge diagnoses of AMI between 2001 and 2005 excluding those who died within the first 30?days after AMI or who had been hospitalised with an AMI in the previous 2?years. A total of 3,008 patients were followed up until death, cancellation of insurance, or the end of the study period on 31 December 2007, whichever came first (median follow-up: 4.2?years).

Results

Drug adherence to single drug groups as determined by proportion of days covered ≥80?% was 21.8?% for antiplatelet drugs, 9.4?% for beta-blockers, 45.6?% for ACE inhibitors or angiotensin II receptor blockers and 45.1?% for lipid-lowering drugs. A total of 924 (39.7?%) patients met our definition of guideline adherence: Drugs available from three of four relevant drug groups on the same day for at least 50?% of the observation time. Of the patients adhering to the guidelines, 17.3?% died and of the non-adherents, 32.4?% died. All-cause mortality was 28?% lower for guideline-adherent patients than for the non-adherent group (adjusted HR 0.72, 95?% CI 0.60–0.86).

Conclusions

In everyday practice, post AMI patients benefit from guideline-oriented treatment, but the percentage of adherent patients should be improved.     

Exposure to phototoxic NSAIDs and quinolones is associated with an increased risk of melanoma

Purpose

Ultraviolet radiation exposure is the most important exogenous risk factor for cutaneous malignancies. It is possible that phototoxic drugs promote the development of cutaneous melanoma (CM) by intensifying the effect of ultraviolet light on the skin. We investigated the association between the use of common systemic phototoxic drugs and development of CM.

Methods

This study was a case–control study in a Dutch population-based cohort. The drug dispensing data was obtained from PHARMO, a Dutch drug dispensing and hospital admissions registry, and linked to PALGA, the nationwide pathology network of the Netherlands. The cases were patients diagnosed with pathologically confirmed primary CM between 1991 and 2004. Controls were sampled from the PHARMO population. Exposure to systemic phototoxic drugs was measured and included antimicrobial agents, diuretics, antipsychotic drugs, antidiabetic drugs, cardiac drugs, antimalarials and nonsteroidal anti-inflammatory drugs (NSAIDs). A multivariate conditional logistic regression analysis was performed to study the association between exposure to phototoxic drugs and CM.

Results

The study population included 1,318 cases and 6,786 controls. Any phototoxic drug during the study period was dispensed for 46 % of the cases and 43 % of the controls (p?=?0.012). The use of quinolones [odds ratio (OR) 1.33, 95 % confidence interval (CI) 1.01–1.76] and propionic acid derivative NSAIDs (OR 1.33, 95 % CI 1.14–1.54) had a positive association with CM.

Conclusions

Our study shows that the use of phototoxic drugs is associated with an increased risk of developing CM. Even a short-term use of phototoxic quinolones and propionic acid derivative NSAIDs may increase the risk for CM. Patient education to promote sun-protective behaviour is essential to avoid immediate adverse effects and possible long-term effects of phototoxic drugs.     

Critical insights into the beneficial and protective actions of the kallikrein–kinin system

Hypertension is characterized by an imbalance between the renin–angiotensin system (RAS) and the kallikrein–kinin system (KKS). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II AT-1 receptor antagonists (also known as sartans or ARBs) are potent modulators of these systems and are highly effective as first-line treatments for hypertension, diabetic nephropathies, and diseases of the brain and coronary arteries. However, these agents are mechanistically distinct and should not be considered interchangeable. In this mini-review, we provide novel insights into the often neglected roles of the KKS in the beneficial, protective, and reparative actions of ACEIs. Indeed, ACEIs are the only antihypertensive drugs that properly reduce the imbalance between the RAS and the KKS, thereby restoring optimal cardiovascular homeostasis and significantly reducing morbidity and the risk of all-cause mortality among individuals affected by hypertension and other cardiovascular diseases.Synopsis and bullet points

• •Hypertension, a disease derived from an imbalance between two endogenous systems, the renin–angiotensin system (RAS) and the kallikrein–kinin system (KKS)
• •Effective mediators of these two systems include the octapeptide angiotensin II (Ang II) and the nonapeptide bradykinin (BK)
• •Disease pathology involves an increase in peripheral resistance (↑PVR), an increase in cardiac output (↑CO), hypertrophy of the heart and peripheral vessels, and nephropathies.
• •Preventive measures include a healthy diet, regular exercise, smoking cessation, and limiting salt and alcohol consumption.
• •Rational therapy consists of drugs that aim not only to reduce blood pressure (BP) but also to decrease morbidity and mortality.
• •The goal of therapy is to inhibit the RAS and potentiate the KKS, both of which can be achieved with ACE Inhibitors (ACEIs), thereby restoring optimal cardiovascular homeostasis.

     

Comparison of Hyperkalemic Risk in Hospitalized Patients Treated with Different Angiotensin Receptor Blockers

Background and Aim

Clinical use of angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) is associated with hyperkalemia as an adverse drug reaction. Although it has significant clinical implications, the incidence and relative risks of hyperkalemia with various ARBs have not yet been fully evaluated. The purpose of this study was to determine the risk of hyperkalemic events in hospitalized patients treated with different ARBs and to compare the risk among them.

Methods

We constructed a retrospective cohort composed of hospitalized adult patients who took ARBs in a single tertiary teaching hospital between April 2004 and March 2010. We estimated the incidence of hyperkalemia (serum potassium level >5.5 mEq/L) with various ARBs, and then compared the risk between them using a multivariate Cox proportional hazard model based on age, sex, Charlson co-morbidity score, baseline serum potassium, underlying diseases, and concomitant drugs.

Results

We identified 6992 evaluable intervals from 5449 patients treated with one of the seven ARBs during hospitalization over the 71-month study period with 2521.6 patient-months. We found 381 hyperkalemic events (5.4%) during the study period and an overall event rate of 15.1/100 patient-months. Moderate to fatal hyperkalemia was relatively rare (>6.0 mEq/L, 2.1% [moderate]; >6.5 mEq/L, 0.9% [severe]; >7.0 mEq/L, 0.3% [fatal]). After adjustment for covariates, telmisartan showed a lower risk of hyperkalemia (hazard ratio 0.67; 95% confidence interval 0.51, 0.89) compared with all other ARBs.

Conclusion

The risk of hyperkalemic events in hospitalized patients treated with different ARBs was defined. Telmisartan showed a relatively lower hyperkalemic risk profile in hospitalized patients compared with other ARBs.     

Dose-Dependent Antihypertensive Efficacy and Tolerability of Perindopril in a Large, Observational, 12-Week, General Practice-Based Study

Background

Current guidelines recommend the use of full therapeutic dosages of antihypertensive agents, or combination therapy, to improve BP control of hypertensive patients in primary healthcare.

Objective

The aim of this study was to assess the dose-dependent antihypertensive efficacy and safety of perindopril 4 and 8 mg/day in the clinical setting.

Study Design and Setting

The CONFIDENCE study was a prospective, observational, multicenter trial. This was a real-world, clinic-based, outpatient study involving 880 general practitioners/primary-care clinics and 113 specialists in Canada.

Patients

The study included untreated or inadequately managed patients with hypertension (i.e. seated BP≥140/90 mmHg, or ≥130/80 mmHg in the presence of diabetes mellitus, renal disease, or proteinuria) without coronary artery disease (CAD).

Intervention

Treatment consisted of perindopril 4 mg/day, uptitrated to 8 mg/day as required for BP control at visit 2, for 12 weeks. Among the patients already being treated at baseline, perindopril either directly replaced all previous ACE inhibitors or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), or was added to antihypertensive treatment with calcium channel blockers (CCBs), diuretics, or β-adrenoceptor antagonists (β-blockers).

Main Outcomes Measures

The primary outcomes were the mean changes in BP from baseline following treatment with perindopril 4 and 8 mg/day as well as the proportion of patients achieving BP control (BP <140/90 mmHg, or <130/80 mmHg in diabetic patients) in the intent-to-treat (ITT) population. Secondary analyses included the incidence of adverse events and compliance.

Results

A total of 8298 hypertensive patients entered the study: 56% with newly diagnosed hypertension and 44% with uncontrolled hypertension. Mean SBP/DBP decreased significantly from baseline (152.5 ±10.8/89.5 ±9 mmHg) over 12 weeks (?18.5/?9.7 mmHg; p < 0.001). At visit 2, 23% of patients were uptitrated to perindopril 8 mg/day, which resulted in an additional mean 10.1/5.3 mmHg BP reduction; this reduction was even greater (15.1/5.7 mmHg) among a separate group of severely hypertensive patients (i.e. SBP >170 mmHg or DBP > 109 mmHg at baseline). Target BP was achieved in 54% of the ITT population. Both perindopril 4 mg/day and perindopril 8 mg/day were well tolerated and compliance was high throughout the study.

Conclusion

In the clinical outpatient setting, perindopril was found to be an effective dose-dependent and well tolerated antihypertensive treatment, with good compliance. Uptitration to the full therapeutic dosage of perindopril is an efficient approach for the management of a broad range of hypertensive patients without CAD.