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1.  Heart Failure Care in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(8):e1001699.
In a systematic review and meta-analysis, Kazem Rahimi and colleagues examine the burden of heart failure in low- and middle-income countries.
Please see later in the article for the Editors' Summary
Background
Heart failure places a significant burden on patients and health systems in high-income countries. However, information about its burden in low- and middle-income countries (LMICs) is scant. We thus set out to review both published and unpublished information on the presentation, causes, management, and outcomes of heart failure in LMICs.
Methods and Findings
Medline, Embase, Global Health Database, and World Health Organization regional databases were searched for studies from LMICs published between 1 January 1995 and 30 March 2014. Additional unpublished data were requested from investigators and international heart failure experts. We identified 42 studies that provided relevant information on acute hospital care (25 LMICs; 232,550 patients) and 11 studies on the management of chronic heart failure in primary care or outpatient settings (14 LMICs; 5,358 patients). The mean age of patients studied ranged from 42 y in Cameroon and Ghana to 75 y in Argentina, and mean age in studies largely correlated with the human development index of the country in which they were conducted (r = 0.71, p<0.001). Overall, ischaemic heart disease was the main reported cause of heart failure in all regions except Africa and the Americas, where hypertension was predominant. Taking both those managed acutely in hospital and those in non-acute outpatient or community settings together, 57% (95% confidence interval [CI]: 49%–64%) of patients were treated with angiotensin-converting enzyme inhibitors, 34% (95% CI: 28%–41%) with beta-blockers, and 32% (95% CI: 25%–39%) with mineralocorticoid receptor antagonists. Mean inpatient stay was 10 d, ranging from 3 d in India to 23 d in China. Acute heart failure accounted for 2.2% (range: 0.3%–7.7%) of total hospital admissions, and mean in-hospital mortality was 8% (95% CI: 6%–10%). There was substantial variation between studies (p<0.001 across all variables), and most data were from urban tertiary referral centres. Only one population-based study assessing incidence and/or prevalence of heart failure was identified.
Conclusions
The presentation, underlying causes, management, and outcomes of heart failure vary substantially across LMICs. On average, the use of evidence-based medications tends to be suboptimal. Better strategies for heart failure surveillance and management in LMICs are needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
A healthy heart pumps about 23,000 liters of blood around the body every day. This blood delivers oxygen and nutrients to the rest of the body and carries carbon dioxide and waste products away from the tissues and organs. A healthy heart is therefore essential for life. Unfortunately, many people (particularly elderly people) develop heart failure, a life-threatening condition in which the heart no longer pumps enough blood to meet all the body's needs because it has become too weak or too stiff to work properly. Heart failure can affect the left, right, or both sides of the heart, and it can develop slowly (chronic heart failure) or quickly (acute heart failure). Its symptoms include swelling (edema) of the feet, ankles, and legs, tiredness, and shortness of breath. Heart failure, which is most commonly caused by coronary heart disease (blockage with fatty deposits of the blood vessels that supply the heart) or high blood pressure (hypertension), cannot be cured. However, lifestyle changes (for example, losing weight and avoiding salty food) and various medications can control heart failure and improve the quality of life of patients.
Why Was This Study Done?
In high-income countries (HICs), heart failure is a common condition that typically consumes 1%–2% of healthcare resources. Experts believe that heart failure may soon become a major public health issue in low- and middle-income countries (LMICs) because fewer people are dying of infectious diseases in these countries than in the past. LMICs need to plan for this eventuality, but little is known about the current burden of heart failure in LMICs. Here, the researchers undertake a systematic review and meta-analysis of published and unpublished information on the presentation, causes, management, and outcomes of heart failure in LMICs. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis uses statistical approaches to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 49 published studies and four unpublished databases that provided information on nearly 240,000 hospitalizations for acute and chronic heart failure in 31 LMICs. Across these LMICs, the average age of patients admitted to hospital for heart failure was 63 years, more than ten years younger than the average admission age in HICs. Differences in mean age at presentation, which ranged from 42 years in Cameroon and Ghana to 75 years in Argentina, largely correlated with the human development index (a measure of national well-being) of individual LMICs. Notably, acute heart failure accounted for 2.2% of all hospital admissions in the LMICs for which data were available. Hypertension was the main cause of heart failure in Africa and the Americas, whereas ischemic heart disease was the main cause in all other regions. More than two-thirds of patients were prescribed diuretics for heart failure, whereas only 57% of patients were treated with angiotensin-converting enzyme inhibitors, only 34% were treated with beta-blockers, and only 32% were treated with mineralocorticoid receptor antagonists, the three treatments currently recommended in guidelines for managing heart failure. Finally, on average, patients admitted to hospital for heart failure in LMICs spent ten days in hospital, and 8.3% of them died in hospital (compared to 6.7% and 4% of similar patients across Europe and the US, respectively).
What Do These Findings Mean?
These findings show that the presentation, causes, management, and outcomes of heart failure vary substantially across LMICs. Importantly, however, these findings reveal that heart failure is already a major burden in LMICs and that the use of recommended medications for heart failure is currently suboptimal in these countries. Because the studies included in this systematic review and meta-analysis set out to answer different research questions and used different methods to diagnose heart failure, the estimates of the burden of heart failure in LMICs provided here may not be completely accurate. Moreover, because the data were derived mainly from urban tertiary referral hospitals, these findings may not reflect the broader picture of heart failure in the community in LMICs. However, although additional studies are needed to completely assess the burden of heart failure in LMICs, the present findings nevertheless highlight the need to implement better strategies for the management of heart failure in LMICs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001699.
This study is further discussed in a PLOS Medicine Perspective by Druin Burch
The US National Heart, Lung, and Blood Institute provides information for patients about heart failure
The UK National Health Service Choices website provides information about all aspects of heart failure
The American Heart Association, a not-for-profit organization, also provides detailed information about heart failure for patients and their carers
The British Heart Foundation, a not-for-profit organization, provides additional information about heart failure, including a personal story about heart failure; further personal stories about heart failure are provided by the not-for-profit organization Healthtalkonline
Heart Failure Matters provides practical information about heart failure for patients, families, and caregivers in several languages; its website includes an animated journey through heart failure and several personal stories about the condition
MedlinePlus provides links to further resources about heart failure (in English and Spanish)
doi:10.1371/journal.pmed.1001699
PMCID: PMC4130667  PMID: 25117081
2.  Cardiovascular and Renal Outcomes of Renin–Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses 
PLoS Medicine  2016;13(3):e1001971.
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
In a systematic review with network meta-analyses, Ferrán Catalá-López and colleagues synthesize published and unpublished data from randomized controlled trials of renin-angiotensin system inhibitors.
Editors' Summary
Background
Chronic high blood pressure can damage blood vessels, heart, and kidneys, and cause cardiovascular and kidney (or renal) disease. Diabetes increases the risk for high blood pressure. An estimated two-thirds of adults with diabetes have high blood pressure or take blood-pressure-reducing drugs (also called antihypertensives). Because diabetes itself increases the risk for heart and kidney diseases, controlling blood pressure is important. Several of the drugs commonly prescribed to patients with diabetes target the renin–angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance. When renal blood flow is low, kidney cells produce renin and secrete it into the blood stream. Renin in the blood generates a protein called angiotensin I. The angiotensin-converting enzyme (ACE) in the lungs subsequently converts angiotensin I to angiotensin II, and angiotensin II docks with its partner, the angiotensin receptor. This then leads to a signaling cascade that causes blood vessels to constrict and the kidneys to secrete water and salt into the blood, resulting in increased blood pressure.
Drugs that interrupt different steps in the cascade can lower blood pressure and thereby prevent cardiovascular and renal disease. In addition to their blood-pressure-lowering effects, some RAS blockers have also been shown to protect heart and kidney function through other mechanisms. RAS blockers fall into three main classes: ACE inhibitors block the conversion of angiotensin I into angiotensin II, angiotensin receptor blockers (ARBs) prevent angiotensin II from activating the angiotensin receptor, and direct renin inhibitors inhibit the production of angiotensin I.
Why Was This Study Done?
As many adults with diabetes are prescribed RAS blockers and likely need to take them or related drugs for the rest of their lives, the question of which drug (or drug combination) has the best results and the least side effects is important. Data from many randomized controlled trials (RCTs, which are the most rigorous clinical tests) have generated results that address this question. Their combined analysis, however, is complicated because the trials often don’t compare all treatments directly, don’t use the exact same treatments in patients with the exact same conditions, or don’t measure the exact same outcomes. Nonetheless, scientists have developed methods to analyze such complex data, including a method called network meta-analysis, which helps to integrate and synthesize diverse results to determine the relative merits of multiple treatments. Here the researchers apply network meta-analysis to all available data from RCTs in which adults with diabetes were given RAS blockers, alone or in combination with other high blood pressure treatments, and that measured cardiovascular or renal outcomes.
What Did the Researchers Do and Find?
The researchers started with a systematic search of the medical literature for RCTs that tested RAS blockers alone or in combination in adults with diabetes. They also contacted the sponsors of many studies to find out whether they had additional data that were not included in the published reports. They included all trials that had at least 100 participants, followed the participants for at least 12 months, and reported cardiovascular or renal outcomes. In all, 71 trials that tested a total of 14 different treatment regimens in 103,120 participants met these criteria. With network meta-analysis, the researchers were able to summarize the results of all these trials in a meaningful way. They did this by integrating direct comparisons of RAS blockers within the same trial (where those were available) with indirect comparisons across all trials. The primary endpoints in their analysis were major cardiovascular outcome (a composite of cardiovascular mortality, nonfatal heart attack, and nonfatal stroke) and progression of renal disease (a composite of end-stage renal disease, doubling of serum creatinine [a marker of reduced kidney function], and all-cause mortality). They also analyzed the individual cardiovascular or renal outcomes separately, but these results carried more uncertainty because fewer patients had the individual, compared with the combined, outcomes.
The researchers found no significant differences in the risk of major cardiovascular outcome between ACE inhibitors and either ARBs or a combination of an ACE inhibitor plus an ARB. Similarly, for the risk of progression of renal disease, no significant differences were detected between ACE inhibitors and any of the remaining therapies, such as ARBs or a combination of an ACE inhibitor plus an ARB. They also found that no RAS blocker strategy was superior to ACE inhibitors with respect to all-cause mortality, cardiovascular mortality, heart attacks, strokes, end-stage renal disease, or doubling of serum creatinine. Overall, any single ACE inhibitor or ARB was equally effective as any other, and just as effective as any drug combination.
What Do These Findings Mean?
The findings reinforce North American and European guidelines that recommend ACE inhibitors and ARBs for antihypertensive therapy in patients with diabetes. The fact that combinations of two drugs had outcomes no better than those of a single ACE inhibitor or ARB—together with results from other studies that reported increased adverse effects in patients who took drug combinations—cautions against the use of combination therapy. The findings also contradict earlier reports suggesting that ARBs may increase the risk of cardiovascular outcomes. There were not enough data comparing direct renin inhibitors (a drug class that was developed more recently and therefore has been studied less) with ACE inhibitors or ARBs to allow strong conclusions; additional research might therefore be warranted.
The analyses here did not consider the costs of any particular drug, or any side effects that were not relevant to the outcomes measured. These factors, together with the results here and a patient’s specific situation, should be taken into account when doctors and their patients discuss and decide appropriate treatments.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001971.
The MedlinePlus has links to information on diabetes
The American Diabetes Association provides information on kidney disease, heart disease, and high blood pressure
The European Society of Cardiology has guidelines on diabetes, heart disease, and high blood pressure
The UK National Institute for Health and Care Excellence has guidelines on renin–angiotensin system drugs
doi:10.1371/journal.pmed.1001971
PMCID: PMC4783064  PMID: 26954482
3.  Geographic Variation in Cardioprotective Antihypertensive Medication Usage in Dialysis Patients 
Background
Despite their high risk for adverse cardiac outcomes, persons on chronic dialysis have been shown to have lower use of antihypertensive medications with cardioprotective properties, such as angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), β-blockers, and calcium channel blockers (CCBs), than might be expected. We constructed a novel database that permits detailed exploration into the demographic, clinical and geographic factors associated with the use these agents of among hypertensive chronic dialysis patients.
Study Design
National cross-sectional retrospective analysis linking Medicaid prescription drug claims with United States Renal Data System core data.
Setting & Participants
48,882 hypertensive chronic dialysis patients who were dually-eligible for Medicaid and Medicare services in 2005.
Factors
Demographics, comorbidities, functional status, and state of residence.
Outcomes
Prevalence of cardioprotective antihypertensive agents in Medicaid pharmacy claims and state-specific observed:expected odds ratios of medication exposure.
Measurements
Factors associated with medication use were modeled using multi-level logistic regression models.
Results
In multivariable analyses, cardioprotective antihypertensive medication exposure was significantly associated with younger age, female sex, non-Caucasian race, intact functional status, and use of in-center hemodialysis. Diabetes was associated with a statistically-significant 28% higher odds of ACE inhibitor/ARB use, but congestive heart failure (CHF) was associated with only a 9% increase in the odds of β-blockers and no increase in ACE inhibitor/ARB use. There was substantial state-by-state variation in use of all classes of agents, with a greater than 2.9-fold difference in adjusted rate odds ratios between the highest- and lowest-prescribing states for ACE inhibitors/ARBs and a 3.6-fold difference for β-blockers.
Limitations
Limited generalizability beyond study population.
Conclusions
Among publicly insured chronic dialysis patients with hypertension, there were marked differences in use rates by state, in part potentially due to differences in Medicaid benefits. However, geographic characteristics were also associated with exposure suggesting clinical uncertainty about the utility of these medications.
doi:10.1053/j.ajkd.2011.02.387
PMCID: PMC3141225  PMID: 21621889
antihypertensive drugs; cardioprotection; dialysis; end stage renal disease; Medicare; Medicaid; Insurance
4.  Enhanced External Counterpulsation (EECP) 
Executive Summary
Objective
To assess the effectiveness, and cost effectiveness of EECP in patients with severe anginal symptoms, secondary to chronic coronary disease, who are unresponsive to exhaustive pharmacotherapy and not candidates for surgical/percutaneous revascularization procedures (e.g., angioplasty, coronary bypass surgery).
To assess the effectiveness, and cost effectiveness of EECP in patients with heart failure.
Clinical Need
Angina
Angina is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back or arm. Angina usually occurs in patients with coronary artery disease (CAD) involving ≥1 large epicardial artery. However it can also occur in people with valvular heart disease, hypertrophic cardiomyopathy, and uncontrolled hypertension.
Conventional approaches to restoring the balance between oxygen supply and demand focus on the disruption of the underlying disease through: drug therapy (β blockers, calcium channel blockers, nitrates, antiplatelet agents, ACE inhibitors, statins); life-style modifications (smoking cessation, weight loss); or revascularization techniques such as coronary artery bypass graft surgery (CABG) or percutaneous coronary interventions (PCI). (1) Limitations of each of these approaches include: adverse drug effects, procedure-related mortality and morbidity, restenosis after PCI, and time dependent graft attrition after CABG. Furthermore, an increasing number of patients are not appropriate candidates for standard revascularization options, due to co-morbid conditions (HF, peripheral vascular disease), poor distal coronary artery targets, and patient preference. The morbidity and mortality associated with repeat surgical revascularization procedures are significantly higher, and often excludes these patients from consideration for further revascularizations. (2)
Patients with CAD who have chronic ischemic symptoms that are unresponsive to both conventional medical therapy and revascularization techniques have refractory angina pectoris. It has been estimated that greater than 100,000 patients each year in the US may be diagnosed as having this condition. (3) Patients with refractory angina have marked limitation of ordinary physical activity or are unable to perform any ordinary physical activity without discomfort (CCS functional class III/IV). Also, there must be some objective evidence of ischemia as demonstrated by exercise treadmill testing, stress imaging studies or coronary physiologic studies. (1)
Dejongste et al. (4)estimated that the prevalence of chronic refractory angina is about 100,000 patients in the United States. This would correspond to approximately 3,800 (100,000 x 3.8% [Ontario is approximately 3.8% of the population of the United States]) patients in Ontario having chronic refractory angina.
Heart Failure
Heart failure results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump.
A recent study (5) revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older.
Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. (6) The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF (7):
Class I: No limitation of physical activity. No symptoms with ordinary exertion.
Class II: Slight limitations of physical activity. Ordinary activity causes symptoms.
Class III: Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.
Class IV: Inability to carry out any physical activity without discomfort. Symptoms at rest.
The National Heart, Lung, and Blood Institute (7) estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. Surveys (8) suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms.
To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses. (6)
The Technology
Patients are typically treated by a trained technician in a medically supervised environment for 1 hour daily for a total of 35 hours over 7 weeks. The procedure involves sequential inflation and deflation of compressible cuffs wrapped around the patient’s calves, lower thighs and upper thighs. In addition to 3 sets of cuffs, the patient has finger plethysmogram and electrocardiogram (ECG) attachments that are connected to a control and display console.
External counterpulsation was used in the United States to treat cardiogenic shock after acute myocardial infarction. (9;10) More recently, an enhanced version namely “enhanced external counterpulsation” (EECP) was introduced as a noninvasive procedure for outpatient treatment of patients with severe, uncontrollable cardiac ischemia. EECP is said to increase coronary perfusion pressure and reduce the myocardial oxygen demand. Currently, EECP is not applicable for all patients with refractory angina pectoris. For example, many patients are considered ineligible for therapy due to co-morbidities, including those with severe pulmonary vascular disease, deep vein thrombosis, phlebitis and irregular heart rhythms, and heart failure. (1)
Very recently, investigation began into EECP as an adjunctive treatment for patients with HF. Anecdotal reports suggested that EECP may benefit patients with coronary disease and left ventricular dysfunction. The safety and effectiveness of EECP in patients with symptomatic heart failure and coronary disease and its role in patients with nonischemic heart failure secondary to LV dysfunction is unclear. Furthermore, the safety and effectiveness of EECP in the different stages of HF and whether it is only for patients who are refractive to pharmacotherapy is unknown.
2003 Health Technology Assessment by the Medical Advisory Secretariat
The Medical Advisory Secretariat health technology assessment (originally published in February 2003) reported on the effectiveness of EECP for patients with angina and HF. The report concluded that there was insufficient evidence to support the use of EECP in patients with refractory stable CCS III/IV angina as well as insufficient evidence to support the use of EECP in patients with HF.
Review Strategy
The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of EECP for the treatment of refractory stable CCS III/IV angina or HF.
The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from December 2002 to March 2006.
A modification of the GRADE approach (11) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study’s design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations.
Summary of Findings
The Cochrane and INAHTA databases yielded 3 HTAs or systematic reviews on EECP treatment (Blue Cross Blue Shield Technology Evaluation Center [BCBS TEC], ECRI, and the Centers for Medicare and Medicaid Services [CMS]). A search of Medline and Embase December 2005 – March 2006 (after the literature search cutoff from the most recent HTA) was conducted using key words enhanced external counterpulsation, EECP, angina, myocardial ischemia, congestive heart failure. This search produced 1 study which met the inclusion criteria. This level 4a study was inferior in quality to the RCT which formed the basis of the 2003 Medical Advisory Secretariat recommendation.
BCBS reviewed the evidence through November 2005 to determine if EECP improves health outcomes for refractory chronic stable angina pectoris or chronic stable HF. (12) BCBS concluded that the available evidence is not sufficient to permit conclusions of the effect of EECP on health outcomes. Both controlled trials had methodologic flaws (MUST EECP and MUST EECP quality of life studies). The case series and observational studies for both indications while suggestive of a treatment benefit from EECP have shortcomings as well.
On March 20 2006, CMS posted their proposed coverage decision memorandum for external counterpulsation therapy. (13) Overall, CMS stated that the evidence is not adequate to conclude that external counterpulsation therapy is reasonable and necessary for:
Canadian Cardiovascular Society Classification (CCSC) II angina
Heart failure
NYHA class II/III stable HF symptoms with an EF≤35%
NYHA class II/III stable HF symptoms with an EF≤40%
NYHA class IV HF
Acute HF
Cardiogenic shock
Acute MI
In January 2005, ECRI (14) stated that there was insufficient evidence available to draw conclusions about the long-term effectiveness of EECP, with respect to morbidity, survival, or quality of life, for any coronary indication (refractory angina, congestive heart failure, cardiogenic shock and acute MI).
GRADE Quality of the Studies
According to the GRADE Working Group criteria, the quality of the trials was examined (Table 1). (11)
Quality refers to the criteria such as the adequacy of allocation concealment, blinding and followup.
Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies.
As stated by the GRADE Working Group, the following definitions were used in grading the quality of the evidence. (11)
GRADE Quality of Studies
Economic Analysis - Literature Review
No economic analysis of EECP was identified in the published literature.
Estimated Prevalence of Angina in Ontario
3,800 patients with chronic refractory angina:
The number of patients with chronic refractory angina in the US is estimated to be approximately 100,000 (4), this corresponds to about 3,800 patients in Ontario (3.8% × 100,000) with refractory angina.
3,800 patients × $7,000 Cdn (approximate cost for a full course of therapy) ~ $26.6M Cdn.
Estimated Prevalence of Heart Failure in Ontario
23,700 patients EF ≤ 0.35:
This estimate is from an expert (personal communication) at the Institute for Clinical Evaluative Sciences (ICES), where they examined a sample of echocardiography studies drawn from a diagnostic lab in 2001. They found that the prevalence of EF ≤ 0.35 was 8.3%, and if generalized to all patients undergoing echocardiography, there would be 23,700 patients.
23,700 patients with EF ≤35% × $7,000 Cdn ~ $166 M Cdn.
Conclusions
There is insufficient evidence to support the effectiveness and safety of EECP treatment for patients with refractory stable CCS III-IV angina or HF.
As per the GRADE Working Group, overall recommendations consider 4 main factors. (11)
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates and the relative value placed on the outcome.
The quality of the evidence.
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise.
Uncertainty about the baseline risk for the population of interest.
The GRADE Working Group also recommends that incremental costs of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms. (11) Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 2 is the overall trade-off between benefits and harms and incorporates any risk/uncertainty.
For angina and heart failure, the overall GRADE and strength of the recommendations is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $26.6 M Cdn or $166 M Cdn respectively while the cost-effectiveness of EECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness.
Overall GRADE and Strength of Recommendation (Including Uncertainty)
PMCID: PMC3379533  PMID: 23074496
5.  Use of Guideline-Recommended Therapies for Heart Failure in the Medicare Population 
Clinical cardiology  2010;33(7):400-405.
Summary
Background
Most information about the use of guideline-recommended therapies for heart failure reflects what occurred at discharge after an inpatient stay.
Research Question
Using a nationally representative, community-dwelling sample of elderly Medicare beneficiaries, we examined how the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), and beta-blockers has changed and factors associated with their use.
Methods
Using data from the Medicare Current Beneficiary Survey cost and use files matched with Medicare claims data, we identified beneficiaries for whom a diagnosis of heart failure was reported between January 1, 2000, and December 31, 2004. Data on medications prescribed during the year of cohort entry were based on patient self-report. We used multivariable logistic regression to explore relationships between the use of ACE inhibitors/ARBs and beta-blockers and patient demographic characteristics.
Results
From 2000 through 2004, the use of ARBs increased from 12% to 19%, and the use of beta-blockers increased from 30% to 41%. The use of ACE inhibitors remained constant at 45%. Beneficiaries who reported having prescription drug insurance coverage were 32% more likely than other beneficiaries to have filled a prescription for an ACE inhibitor or ARB and 26% more likely to have filled a prescription for a beta-blocker.
Conclusions
Although the use of guideline-recommended therapies for heart failure has increased, it remains suboptimal.
doi:10.1002/clc.20760
PMCID: PMC3740389  PMID: 20641116
Evidence-Based Practice; Guidelines as Topic; Heart Failure; Medicare
6.  Heart failure 
BMJ Clinical Evidence  2011;2011:0204.
Introduction
Heart failure occurs in 3% to 4% of adults aged over 65 years, usually as a consequence of coronary artery disease or hypertension, and causes breathlessness, effort intolerance, fluid retention, and increased mortality. The 5-year mortality in people with systolic heart failure ranges from 25% to 75%, often owing to sudden death following ventricular arrhythmia. Risks of cardiovascular events are increased in people with left ventricular systolic dysfunction (LVSD) or heart failure.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of multidisciplinary interventions for heart failure? What are the effects of exercise in people with heart failure? What are the effects of drug treatments for heart failure? What are the effects of devices for treatment of heart failure? What are the effects of coronary revascularisation for treatment of heart failure? What are the effects of drug treatments in people at high risk of heart failure? What are the effects of treatments for diastolic heart failure? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 80 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aldosterone receptor antagonists, amiodarone, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, anticoagulation, antiplatelet agents, beta-blockers, calcium channel blockers, cardiac resynchronisation therapy, coronary revascularisation, digoxin (in people already receiving diuretics and angiotensin-converting enzyme inhibitors), exercise, hydralazine plus isosorbide dinitrate, implantable cardiac defibrillators, multidisciplinary interventions, non-amiodarone antiarrhythmic drugs, and positive inotropes (other than digoxin).
Key Points
Heart failure occurs in 3% to 4% of adults aged over 65 years, usually as a consequence of coronary artery disease or hypertension, and causes breathlessness, effort intolerance, fluid retention, and increased mortality. The 5-year mortality in people with systolic heart failure ranges from 25% to 75%, often owing to sudden death following ventricular arrhythmia. Risks of cardiovascular events are increased in people with left ventricular systolic dysfunction (LVSD) or heart failure.
Multidisciplinary interventions may reduce admissions to hospital and mortality in people with heart failure compared with usual care. Exercise may reduce admissions to hospital due to heart failure compared with usual care. However, long-term benefits of these interventions remain unclear.
ACE inhibitors, angiotensin II receptor blockers, and beta-blockers reduce mortality and hospital admissions from heart failure compared with placebo, with greater absolute benefits seen in people with more severe heart failure. Combined treatment with angiotensin II receptor blockers and ACE inhibitors may lead to a greater reduction in hospital admission for heart failure compared with ACE inhibitor treatment alone.
Aldosterone receptor antagonists (spironolactone, eplerenone, and canrenoate) may reduce all-cause mortality in people with heart failure, but increase the risk of hyperkalaemia.
Digoxin slows the progression of heart failure compared with placebo, but may not reduce mortality.
Hydralazine plus isosorbide dinitrate may improve survival and quality-of-life scores compared with placebo in people with chronic congestive heart failure.
We don't know whether amiodarone, anticoagulants, or antiplatelets are effective at reducing mortality or hospital re-admission rates.
CAUTION: Positive inotropic agents (other than digoxin), calcium channel blockers, and antiarrhythmic drugs (other than amiodarone and beta-blockers) may all increase mortality and should be used with caution, if at all, in people with systolic heart failure.
Implantable cardiac defibrillators and cardiac resynchronisation therapy can reduce mortality in people with heart failure who are at high risk of ventricular arrhythmias. However, studies evaluating cardiac resynchronisation therapy were performed in centres with considerable experience, which may have overestimated the benefits.
We don't know how coronary revascularisation and drug treatment compare for reducing mortality in people with heart failure and left ventricular dysfunction because all the trials assessing this comparison were conducted before ACE inhibitors, aspirin, beta-blockers, and statins were in routine use, thus limiting their applicability to current clinical practice.
ACE inhibitors delay the onset of symptomatic heart failure, reduce cardiovascular events, and improve long-term survival in people with asymptomatic LVSD compared with placebo. Angiotensin II receptor blockers and ACE inhibitors seem equally effective at reducing all-cause mortality and cardiovascular mortality in people at high risk of heart failure.The combination of angiotensin II receptor blockers and ACE inhibitors seems no more effective than ACE inhibitors alone and causes more adverse effects.
ACE inhibitors or angiotensin II receptor blockers seem no more effective at reducing mortality or rate of hospital admissions for cardiovascular events in people with diastolic heart failure compared with placebo. We don't know whether treatments other than angiotensin II receptor blockers are beneficial in reducing mortality in people with diastolic heart failure as we found only one trial.
PMCID: PMC3275321  PMID: 21878135
7.  Risk of cardiovascular events after initiation of long-acting bronchodilators in patients with chronic obstructive lung disease: A population-based study 
SAGE Open Medicine  2016;4:2050312116671337.
Objectives:
Long-acting bronchodilators are mainstay treatment for moderate to severe chronic obstructive pulmonary disease. A growing body of evidence indicates an increased risk of cardiovascular events upon initiation of these medications. We hypothesize that this risk is higher in patients with chronic obstructive pulmonary disease who had a preexisting cardiovascular disease regardless of receipt of any cardiovascular medication.
Methods:
A retrospective cohort of patients with a diagnosis of chronic obstructive pulmonary disease based on two outpatient visits or one inpatient visit for chronic obstructive pulmonary disease (International Classification of Diseases, 9th Edition, Clinical Modification codes 491.x, 492.x, 496) in any year between 2001 and 2012 from a commercial insurance database. We then selected those initiating long-acting bronchodilator treatments between April 2001 and September 2012. Each patient had a 1 year look back period to determine history of cardiovascular disease or cardiovascular disease treatment from the time of first prescription of long-acting beta agonist, long-acting muscarinic antagonist, or long-acting beta agonist combined with inhaled corticosteroids. Patients were followed for 90 days for hospitalizations or emergency department visits for cardiovascular event. The cohort was divided into four groups based on the presence of cardiovascular disease (including ischemic heart disease, hypertension, ischemic stroke, heart failure, tachyarrhythmias and artery disease based on International Classification of Diseases, 9th Edition, Clinical Modification codes) and cardiovascular disease treatment defined as acetylsalicylic acid, beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antiplatelet, anticoagulants, calcium channel blockers, nitrate, digoxin, diuretics, antiarrhythmics or statins. Odds of emergency department visit or hospitalization in the 90 days after prescription were examined using multivariable logistic regression models.
Results:
Of 61,651 eligible patients, 36,755 (59.6%) had cardiovascular disease and were on cardiovascular disease treatment (Group 1), 7250 (11.8%) had cardiovascular disease without cardiovascular disease treatment (Group 2), 4715 (7.7%) had no cardiovascular disease but had cardiovascular disease treatment (Group 3) and 12,931 (21%) had no cardiovascular disease and no treatment (Group 4). In these four groups, the unadjusted risk of emergency department visit or hospitalization for cardiovascular disease within 90 days of initiation was 5.45%, 2.95%, 1.55% and 0.96%, respectively. In multivariable analysis, the adjusted odds ratio with 95% confidence interval of emergency department visit/hospitalization for each of the first three groups to those with no cardiovascular disease and no treatment were 3.50 (95% confidence interval, 2.89–4.24), 2.15 (95% confidence interval, 1.71–2.70) and 1.36 (95% confidence interval, 1.01–1.82), respectively.
Conclusion:
The risk of cardiovascular events after initiation of long-acting bronchodilators is highest in patients with baseline cardiovascular disease and on cardiovascular disease medications. Clinicians should be cautious while prescribing these medications in patients with preexisting cardiovascular disease.
doi:10.1177/2050312116671337
PMCID: PMC5052927  PMID: 27757229
Chronic obstructive lung disease; long-acting bronchodilators; cardiovascular disease; long-acting beta agonist; long-acting muscarinic antagonist; long-acting beta agonist-inhaled corticosteroids
8.  Heart failure 
BMJ Clinical Evidence  2010;2010:0204.
Introduction
Heart failure occurs in 3% to 4% of adults aged over 65 years, usually as a consequence of coronary artery disease or hypertension, and causes breathlessness, effort intolerance, fluid retention, and increased mortality. The 5-year mortality in people with systolic heart failure ranges from 25% to 75%, often owing to sudden death following ventricular arrhythmia. Risks of cardiovascular events are increased in people with left ventricular systolic dysfunction (LVSD) or heart failure.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug treatments, and of drug and invasive treatments, for heart failure? What are the effects of angiotensin-converting enzyme inhibitors in people at high risk of heart failure? What are the effects of treatments for diastolic heart failure? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 85 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aldosterone receptor antagonists, amiodarone, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, anticoagulation, antiplatelet agents, beta-blockers, calcium channel blockers, cardiac resynchronisation therapy, digoxin (in people already receiving diuretics and angiotensin-converting enzyme inhibitors), exercise, hydralazine plus isosorbide dinitrate, implantable cardiac defibrillators, multidisciplinary interventions, non-amiodarone antiarrhythmic drugs, and positive inotropes (other than digoxin).
Key Points
Heart failure occurs in 3% to 4% of adults aged over 65 years, usually as a consequence of coronary artery disease or hypertension, and causes breathlessness, effort intolerance, fluid retention, and increased mortality. The 5-year mortality in people with systolic heart failure ranges from 25% to 75%, often owing to sudden death following ventricular arrhythmia. Risks of cardiovascular events are increased in people with left ventricular systolic dysfunction (LVSD) or heart failure.
Multidisciplinary interventions and exercise may reduce admissions to hospital and mortality in people with heart failure compared with usual care, although long-term benefits remain unclear.
Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and beta-blockers reduce mortality and hospital admissions from heart failure compared with placebo, with greater absolute benefits seen in people with more severe heart failure. Combined treatment with angiotensin II receptor blockers and ACE inhibitors may lead to a greater reduction in admission for heart failure compared with ACE inhibitor treatment alone.
Aldosterone receptor antagonists (spironolactone, eplerenone, and canrenoate) may reduce all-cause mortality in people with heart failure, but increase the risk of hyperkalaemia.
Digoxin slows the progression of heart failure compared with placebo, but may not reduce mortality.
Hydralazine plus isosorbide dinitrate may improve survival and quality-of-life scores compared with placebo in people with chronic congestive heart failure.
ACE inhibitors delay the onset of symptomatic heart failure, reduce cardiovascular events, and improve long-term survival in people with asymptomatic LVSD compared with placebo.
We don't know whether amiodarone, anticoagulants, or antiplatelets are effective at reducing mortality or hospital re-admission rates.
We don't know whether angiotensin II receptor blockers reduce mortality or rate of hospital admissions for cardiovascular events in people with diastolic heart failure. We don't know whether treatments with other angiotensin II receptor blockers are beneficial in reducing mortality in people with diastolic heart failure.
CAUTION: Positive inotropic agents (other than digoxin), calcium channel blockers, and antiarrhythmic drugs (other than amiodarone and beta-blockers) may all increase mortality and should be used with caution, if at all, in people with systolic heart failure.
Implantable cardiac defibrillators and cardiac resynchronisation therapy can reduce mortality in people with heart failure who are at high risk of ventricular arrhythmias. However, studies evaluating cardiac resynchronisation therapy were performed in centres with considerable experience, which may have overestimated the benefits.
PMCID: PMC2907608  PMID: 21718583
9.  Biventricular Pacing (Cardiac Resynchronization Therapy) 
Executive Summary
Issue
In 2002, (before the establishment of the Ontario Health Technology Advisory Committee), the Medical Advisory Secretariat conducted a health technology policy assessment on biventricular (BiV) pacing, also called cardiac resynchronization therapy (CRT). The goal of treatment with BiV pacing is to improve cardiac output for people in heart failure (HF) with conduction defect on ECG (wide QRS interval) by synchronizing ventricular contraction. The Medical Advisory Secretariat concluded that there was evidence of short (6 months) and longer-term (12 months) effectiveness in terms of cardiac function and quality of life (QoL). More recently, a hospital submitted an application to the Ontario Health Technology Advisory Committee to review CRT, and the Medical Advisory Secretariat subsequently updated its health technology assessment.
Background
Chronic HF results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump. It is estimated that 1% to 5% of the general population (all ages) in Europe have chronic HF. (1;2) About one-half of the patients with HF are women, and about 40% of men and 60% of women with this condition are aged older than 75 years.
The incidence (i.e., the number of new cases in a specified period) of chronic HF is age dependent: from 1 to 5 per 1,000 people each year in the total population, to as high as 30 to 40 per 1,000 people each year in those aged 75 years and older. Hence, in an aging society, the prevalence (i.e., the number of people with a given disease or condition at any time) of HF is increasing, despite a reduction in cardiovascular mortality.
A recent study revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. (3) Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older.
Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. (2;4) The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF (2;5):
Class I: No limitation of physical activity. No symptoms with ordinary exertion.
Class II: Slight limitations of physical activity. Ordinary activity causes symptoms.
Class III: Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.
Class IV: Inability to carry out any physical activity without discomfort. Symptoms at rest.
The National Heart, Lung, and Blood Institute estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. (5) Surveys (2) suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms.
Overall, patients with chronic, stable HF have an annual mortality rate of about 10%. (2) One-third of patients with new-onset HF will die within 6 months of diagnosis. These patients do not survive to enter the pool of those with “chronic” HF. About 60% of patients with incident HF will die within 3 years, and there is limited evidence that the overall prognosis has improved in the last 15 years.
To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses.
The Technology
Owing to the limitations of drug therapy, cardiac transplantation and device therapies have been used to try to improve QoL and survival of patients with chronic HF. Ventricular pacing is an emerging treatment option for patients with severe HF that does not respond well to medical therapy. Traditionally, indications for pacing include bradyarrhythmia, sick sinus syndrome, atrioventricular block, and other indications, including combined sick sinus syndrome with atrioventricular block and neurocardiogenic syncope. Recently, BiV pacing as a new, adjuvant therapy for patients with chronic HF and mechanical dyssynchrony has been investigated. Ventricular dysfunction is a sign of HF; and, if associated with severe intraventricular conduction delay, it can cause dyssynchronous ventricular contractions resulting in decreased ventricular filling. The therapeutic intent is to activate both ventricles simultaneously, thereby improving the mechanical efficiency of the ventricles.
About 30% of patients with chronic HF have intraventricular conduction defects. (6) These conduction abnormalities progress over time and lead to discoordinated contraction of an already hemodynamically compromised ventricle. Intraventricular conduction delay has been associated with clinical instability and an increased risk of death in patients with HF. (7) Hence, BiV pacing, which involves pacing left and right ventricles simultaneously, may provide a more coordinated pattern of ventricular contraction and thereby potentially reduce QRS duration, and intraventricular and interventricular asynchrony. People with advanced chronic HF, a wide QRS complex (i.e., the portion of the electrocardiogram comprising the Q, R, and S waves, together representing ventricular depolarization), low left ventricular ejection fraction and contraction dyssynchrony in a viable myocardium and normal sinus rhythm, are the target patients group for BiV pacing. One-half of all deaths in HF patients are sudden, and the mode of death is arrhythmic in most cases. Internal cardioverter defibrillators (ICDs) combined with BiV pacemakers are therefore being increasingly considered for patients with HF who are at high risk of sudden death.
Current Implantation Technique for Cardiac Resynchronization
Conventional dual-chamber pacemakers have only 2 leads: 1 placed in the right atrium and the other in the right ventricle. The technique used for BiV pacemaker implantation also uses right atrial and ventricular pacing leads, in addition to a left ventricle lead advanced through the coronary sinus into a vein that runs along the ventricular free wall. This permits simultaneous pacing of both ventricles to allow resynchronization of the left ventricle septum and free wall.
Mode of Operation
Permanent pacing systems consist of an implantable pulse generator that contains a battery and electronic circuitry, together with 1 (single-chamber pacemaker) or 2 (dual-chamber pacemaker) leads. Leads conduct intrinsic atrial or ventricular signals to the sensing circuitry and deliver the pulse generator charge to the myocardium (muscle of the heart).
Complications of Biventricular Pacemaker Implantation
The complications that may arise when a BiV pacemaker is implanted are similar to those that occur with standard pacemaker implantation, including pneumothorax, perforation of the great vessels or the myocardium, air embolus, infection, bleeding, and arrhythmias. Moreover, left ventricular pacing through the coronary sinus can be associated with rupture of the sinus as another complication.
Conclusion of 2003 Review of Biventricular Pacemakers by the Medical Advisory Secretariat
The randomized controlled trials (RCTs) the Medical Advisory Secretariat retrieved analyzed chronic HF patients that were assessed for up to 6 months. Other studies have been prospective, but nonrandomized, not double-blinded, uncontrolled and/or have had a limited or uncalculated sample size. Short-term studies have focused on acute hemodynamic analyses. The authors of the RCTs reported improved cardiac function and QoL up to 6 months after BiV pacemaker implantation; therefore, there is level 1 evidence that patients in ventricular dyssynchrony who remain symptomatic after medication might benefit from this technology. Based on evidence made available to the Medical Advisory Secretariat by a manufacturer, (8) it appears that these 6-month improvements are maintained at 12-month follow-up.
To date, however, there is insufficient evidence to support the routine use of combined ICD/BiV devices in patients with chronic HF with prolonged QRS intervals.
Summary of Updated Findings Since the 2003 Review
Since the Medical Advisory Secretariat’s review in 2003 of biventricular pacemakers, 2 large RCTs have been published: COMPANION (9) and CARE-HF. (10) The characteristics of each trial are shown in Table 1. The COMPANION trial had a number of major methodological limitations compared with the CARE-HF trial.
Characteristics of the COMPANION and CARE-HF Trials*
COMPANION; (9) CARE-HF. (10)
BiV indicates biventricular; ICD, implantable cardioverter defibrillator; EF, ejection fraction; QRS, the interval representing the Q, R and S waves on an electrocardiogram; FDA, United States Food and Drug Administration.
Overall, CARE-HF showed that BiV pacing significantly improves mortality, QoL, and NYHA class in patients with severe HF and a wide QRS interval (Tables 2 and 3).
CARE-HF Results: Primary and Secondary Endpoints*
BiV indicates biventricular; NNT, number needed to treat.
Cleland JGF, Daubert J, Erdmann E, Freemantle N, Gras D, Kappenberger L et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure (CARE-HF). New England Journal of Medicine 2005; 352:1539-1549; Copyright 2003 Massachusettes Medical Society. All rights reserved. (10)
CARE H-F Results: NYHA Class and Quality of Life Scores*
Minnesota Living with Heart Failure scores range from 0 to 105; higher scores reflect poorer QoL.
European Quality of Life–5 Dimensions scores range from -0.594 to 1.000; 1.000 indicates fully healthy; 0, dead
Cleland JGF, Daubert J, Erdmann E, Freemantle N, Gras D, Kappenberger L et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure (CARE-HF). New England Journal of Medicine 2005; 352:1539-1549; Copyright 2005 Massachusettes Medical Society. All rights reserved.(10)
GRADE Quality of Evidence
The quality of these 3 trials was examined according to the GRADE Working Group criteria, (12) (Table 4).
Quality refers to criteria such as the adequacy of allocation concealment, blinding, and follow-up.
Consistency refers to the similarity of estimates of effect across studies. If there is an important unexplained inconsistency in the results, confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect, and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker, or have more comorbid conditions than do the people in the studies.
As stated by the GRADE Working Group, (12) the following definitions were used in grading the quality of the evidence:
High: Further research is very unlikely to change our confidence on the estimate of effect.
Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low: Any estimate of effect is very uncertain.
Quality of Evidence: CARE-HF and COMPANION
Conclusions
Overall, there is evidence that BiV pacemakers are effective for improving mortality, QoL, and functional status in patients with NYHA class III/IV HF, an EF less than 0.35, a QRS interval greater than 120 ms, who are refractory to drug therapy.
As per the GRADE Working Group, recommendations considered the following 4 main factors:
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates, and the relative value placed on the outcome
The quality of the evidence (Table 4)
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise
Uncertainty about the baseline risk for the population of interest
The GRADE Working Group also recommends that incremental costs of health care alternatives should be considered explicitly alongside the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 5 shows the overall trade-off between benefits and harms and incorporates any risk/uncertainty.
For BiV pacing, the overall GRADE and strength of the recommendation is moderate: the quality of the evidence is moderate/high (because of some uncertainty due to methodological limitations in the study design, e.g., no blinding), but there is also some risk/uncertainty in terms of the estimated prevalence and wide cost-effectiveness estimates (Table 5).
For the combination BiV pacing/ICD, the overall GRADE and strength of the recommendation is weak—the quality of the evidence is low (because of uncertainty due to methodological limitations in the study design), but there is also some risk/uncertainty in terms of the estimated prevalence, high cost, and high budget impact (Table 5). There are indirect, low-quality comparisons of the effectiveness of BiV pacemakers compared with the combination BiV/ICD devices.
A stronger recommendation can be made for BiV pacing only compared with the combination BiV/ICD device for patients with an EF less than or equal to 0.35, and a QRS interval over or equal to 120 ms, and NYHA III/IV symptoms, and refractory to optimal medical therapy (Table 5).
There is moderate/high-quality evidence that BiV pacemakers significantly improve mortality, QoL, and functional status.
There is low-quality evidence that combined BiV/ICD devices significantly improve mortality, QoL, and functional status.
To date, there are no direct comparisons of the effectiveness of BiV pacemakers compared with the combined BiV/ICD devices in terms of mortality, QoL, and functional status.
Overall GRADE and Strength of Recommendation
BiV refers to biventricular; ICD, implantable cardioverter defibrillator; NNT, number needed to treat.
PMCID: PMC3382419  PMID: 23074464
10.  Characteristics, Outcomes and Predictors of Long-Term Mortality for Patients Hospitalized for Acute Heart Failure: A Report From the Korean Heart Failure Registry 
Korean Circulation Journal  2011;41(7):363-371.
Background and Objectives
Acute heart failure (AHF) is associated with a poor prognosis and it requires repeated hospitalizations. However, there are few studies on the characteristics, treatment and prognostic factors of AHF. The aims of this study were to describe the clinical characteristics, management and outcomes of the patients hospitalized for AHF in Korea.
Subjects and Methods
We analyzed the clinical data of 3,200 hospitalization episodes that were recorded between June 2004 and April 2009 from the Korean Heart Failure (KorHF) Registry database. The mean age was 67.6±14.3 years and 50% of the patients were female.
Results
Twenty-nine point six percent (29.6%) of the patients had a history of previous HF and 52.3% of the patients had ischemic heart disease. Left ventricular ejection fraction (LVEF) was reported for 89% of the patients. The mean LVEF was 38.5±15.7% and 26.1% of the patients had preserved systolic function (LVEF ≥50%), which was more prevalent in the females (34.0% vs. 18.4%, respectively, p<0.001). At discharge, 58.6% of the patients received beta-blockers (BB), 53.7% received either angiotensin converting enzyme-inhibitors or angiotensin receptor blockers (ACEi/ARB), and 58.4% received both BB and ACEi/ARB. The 1-, 2-, 3- and 4-year mortality rates were 15%, 21%, 26% and 30%, respectively. Multivariate analysis revealed that advanced age {hazard ratio: 1.023 (95% confidence interval: 1.004-1.042); p=0.020}, a previous history of heart failure {1.735 (1.150-2.618); p=0.009}, anemia {1.973 (1.271-3.063); p=0.002}, hyponatremia {1.861 (1.184-2.926); p=0.007}, a high level of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) {3.152 (1.450-6.849); p=0.004} and the use of BB at discharge {0.599 (0.360-0.997); p=0.490} were significantly associated with total death.
Conclusion
We present here the characteristics and prognosis of an unselected population of AHF patients in Korea. The long-term mortality rate was comparable to that reported in other countries. The independent clinical risk factors included age, a previous history of heart failure, anemia, hyponatremia, a high NT-proBNP level and taking BB at discharge.
doi:10.4070/kcj.2011.41.7.363
PMCID: PMC3152730  PMID: 21860637
Heart failure; Registries; Outcome
11.  The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To update the evidence-based recommendations for the prevention and management of hypertension in adults for 2009.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease.
EVIDENCE:
A Cochrane collaboration librarian conducted an independent MEDLINE search from 2007 to August 2008 to update the 2008 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to less than 2300 mg (100 mmol)/day (and 1500 mg to 2300 mg [65 mmol to 100 mmol]/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patient’s global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as the initial treatment of hypertension if the systolic blood pressure is 20 mmHg above the target or if the diastolic blood pressure is 10 mmHg above the target. The combination of ACE inhibitors and ARBs should not be used. Other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.
PMCID: PMC2707169  PMID: 19417859
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
12.  Evidence-based cardiovascular care in the community: A population-based cross-sectional study 
Background
Ischaemic heart disease and congestive heart failure are common and important conditions in family practice. Effective treatments may be underutilized, particularly in women and the elderly. The objective of the study was to determine the rate of prescribing of evidence-based cardiovascular medications and determine if these differed by patient age or sex.
Methods
We conducted a two-year cross-sectional study involving all hospitals in the province of Nova Scotia, Canada. Subjects were all patients admitted with ischaemic heart disease with or without congestive heart failure between 15 October 1997 and 14 October 1999. The main measure was the previous outpatient use of recommended medications. Chi-square analyses followed by multivariate logistic regression analyses were used to examine age-sex differences.
Results
Usage of recommended medications varied from approximately 60% for beta-blockers and angiotensin converting enzyme (ACE) inhibitors to 90% for antihypertensive agents. Patients aged 75 and over were significantly less likely than younger patients to be taking any of the medication classes. Following adjustment for age, there were no significant differences in medication use by sex except among women aged 75 and older who were more likely to be taking beta-blockers than men in the same age group.
Conclusions
The use of evidence-based cardiovascular medications is rising and perhaps approaching reasonable levels for some drug classes. Family physicians should ensure that all eligible patients (prior myocardial infarction, congestive failure) are offered beta-blockers or ACE inhibitors.
doi:10.1186/1471-2296-5-6
PMCID: PMC416476  PMID: 15059290
13.  SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR): A Multi-Center, Retrospective, Observational Study 
PLoS ONE  2014;9(1):e86596.
Background
Clinical practice guidelines have been slowly and inconsistently applied in clinical practice, and certain evidence-based, guideline-driven therapies for heart failure (HF) have been significantly underused. The purpose of this study was to survey guideline compliance and its effect on clinical outcomes in the treatment of systolic HF in Korea.
Method and Results
The SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR) trial was a multi-center, retrospective, observational study on subjects with systolic HF (ejection fraction <45%) admitted to 23 university hospitals. The guideline adherence indicator (GAI) was defined as a performance measure on the basis of 3 pharmacological classes: angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), beta-blocker (BB), and aldosterone antagonist (AA). Based on the overall adherence percentage, subjects were divided into 2 groups: those with good guideline adherence (GAI ≥50%) and poor guideline adherence (GAI <50%). We included 1319 regional participants as representatives of the standard population from the Korean national census in 2008. Adherence to drugs at discharge was as follows: ACEI or ARB, 89.7%; BB, 69.2%; and AA, 65.9%. Overall, 82.7% of the patients had good guideline adherence. Overall mortality and re-hospitalization rates at 1 year were 6.2% and 37.4%, respectively. Survival analysis by log-rank test showed a significant difference in event-free survival rate of mortality (94.7% vs. 89.8%, p = 0.003) and re-hospitalization (62.3% vs. 56.4%, p = 0.041) between the good and poor guideline-adherence groups.
Conclusions
Among patients with systolic HF in Korea, adherence to pharmacologic treatment guidelines as determined by performance measures, including prescription of ACEI/ARB and BB at discharge, was associated with improved clinical outcomes.
doi:10.1371/journal.pone.0086596
PMCID: PMC3903552  PMID: 24475154
14.  Management of heart failure: evidence versus practice. Does current prescribing provide optimal treatment for heart failure patients? 
Heart failure is an increasingly common and costly chronic disorder, with a rising prevalence of at least 2% in populations over the age of 45 years, mortality rates that are as poor as common solid cancers, and very high health care utilisation costs. Despite increased evidence supporting a range of effective interventions, predominantly therapeutic, there remain significant degrees of physician underperformance in terms of heart failure diagnosis and management. Until the early 1990s, the management of heart failure was largely confined to the symptomatic relief of patients with well established heart failure in fluid overload. The introduction of angiotensin-converting enzyme (ACE) inhibitors provided the first treatments that beneficially altered the prognosis of patients with the most common expression of heart failure, namely established systolic dysfunction, whether symptomatic or asymptomatic. Evidence has now extended these benefits to delaying progression of heart failure and reducing hospitalisation. Much of our understanding of the pathophysiology of heart failure stems from these studies. More recent data has clarified the limited role of digoxin, the important benefits of beta-blockade and aldosterone blockers as adjuvants to ACE inhibition, and the emerging evidence on angiotensin II antagonists. There are, in contrast to these positive findings, reliable data from Europe and North America revealing significant underperformance of primary care and hospital physicians in heart failure diagnosis and management, with evidence of underuse and underdosing of evidence-based therapies. Limited qualitative data suggest the reasons for this underperformance are complex and relate to lack of access to objective testing of ventricular function and exaggerated concerns over treatment risks and side-effects. Heart failure represents a complex cluster of aetiologies and risks that are not easy to correctly identify, even in specialist settings. Since there is now powerful evidence on how heart failure can be modified and improved, explicit guidance is needed for which suspected patients should be referred, for confirmation of diagnosis and advice on appropriate treatment regimes, and for which patients can be handled mainly within primary care but with enhanced access to objective non-invasive tests to improve diagnostic reliability and to stratify patients to evidence-based therapies. Current evidence suggests that in North America and Europe today primary care physicians do underperform in their management of patients with heart failure, often owing to factors outside of their immediate control.
PMCID: PMC1313804  PMID: 11050792
15.  Utilization of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) in patients diagnosed with diabetes: Analysis from the National Ambulatory Medical Care Survey 
Preventive Medicine Reports  2016;3:166-170.
Objective
The objective of this study was to determine if a difference exists in the proportion of visits for the prescribing of angiotensin converting enzyme inhibitors (ACEI), or angiotensin receptor blockers (ARBs) in diabetic patients during 2007–2010.
Methods
This retrospective, cross-sectional, observational study included adults diagnosed with diabetes mellitus from the National Ambulatory Medical Care Survey (NAMCS) during 2007–2010. Weighted chi-square tests and a multivariable logistic regression model were used to analyze associations between ACEI/ARB prescriptions and predictors of interest. Odds ratios and 95% confidence intervals were reported.
Results
An unweighted total of 13,590 outpatient ambulatory care visits were identified for adult patients with diabetes without contraindications to ACEIs or ARBs in the NAMCS for the years studied. No statistically significant increase in the proportion of visits with an ACEI/ARB prescription was identified for years 2007–2010 (28.1% in 2007 to 32.2% in 2010). Females (OR 0.78, 95% CI 0.69- 0.89), patients 18–39 years old (OR 0.56, 95% CI 0.43- 0.75), and Medicare users (OR 0.81, 95% CI 0.70- 0.94) were significantly less likely to receive an ACEI/ARB prescription. Patients with hypertension (OR 2.80, 95% CI 2.39-3.29), hyperlipidemia (OR 1.42, 95% CI 1.22-1.65), and ischemic heart disease (OR 1.36, 95% CI 1.10-1.70) were significantly more likely to receive an ACEI/ARB prescription.
Conclusions
Despite extensive evidence showing the benefits of ACEI/ARB medications in diabetic patients, disparities of treatment remain evident.
Highlights
•Assessed ACEI/ARB prescriptions in diabetic patients for ADA guideline adherence•A low percentage of patients prescribed an ACEI/ARB (28.1% in 2007–32.2% in 2010)•Females, age 18–39, and Medicare users less likely to receive ACEI/ARB prescription•Hypertension, hyperlipidemia and IHD: more likely to receive ACEI/ARB prescription•Disparities in ACEI/ARB prescriptions remain evident
doi:10.1016/j.pmedr.2016.01.005
PMCID: PMC4929215  PMID: 27419010
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; NAMCS, National Ambulatory Medical Care Survey; ADA, American Diabetes Association; OR, odds ratio; CI, confidence interval; NCHS, National Center for Health Statistics; ACE Inhibitor; ARB; NAMCS; diabetes
16.  Fixed-Dose Combinations of Renin–Angiotensin System Inhibitors and Calcium Channel Blockers in the Treatment of Hypertension 
Medicine  2015;94(51):e2355.
Abstract
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.
doi:10.1097/MD.0000000000002355
PMCID: PMC4698000  PMID: 26705234
17.  An angiotensin II receptor blocker–calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone 
Kidney International  2012;83(1):167-176.
The OSCAR study was a multicenter, prospective randomized open-label blinded end-point study of 1164 Japanese elderly hypertensive patients comparing the efficacy of angiotensin II receptor blocker (ARB) uptitration to an ARB plus calcium channel blocker (CCB) combination. In this prospective study, we performed prespecified subgroup analysis according to baseline estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) defined as an eGFR <60 ml/min per 1.73 m2. Blood pressure was lower in the combined therapy than in the high-dose ARB cohort in both groups with and without CKD. In patients with CKD, significantly more primary events (a composite of cardiovascular events and noncardiovascular death) occurred in the high-dose ARB group than in the combination group (30 vs. 16, respectively, hazard ratio 2.25). Significantly more cerebrovascular and more heart failure events occurred in the high-dose ARB group than in the combination group. In patients without CKD, however, the incidence of primary events was similar between the two treatments. The treatment-by-subgroup interaction was significant. Allocation to the high-dose ARB was a significant independent prognostic factor for primary events in patients with CKD. Thus, the ARB plus CCB combination conferred greater benefit in prevention of cardiovascular events in patients with CKD compared with high-dose ARB alone. Our findings provide new insight into the antihypertensive strategy for elderly hypertensive patients with CKD.
doi:10.1038/ki.2012.326
PMCID: PMC3538966  PMID: 23051740
cardiovascular disease; CKD; combination therapy; high-dose ARB; hypertension
18.  In-Hospital Cardiology Consultation and Evidence-Based Care for Nursing Home Residents with Heart Failure 
Objectives
To determine the association between cardiology consultation and evidence-based care for nursing home (NH) residents with heart failure (HF).
Participants
Hospitalized NH residents (n= 646) discharged from 106 Alabama hospitals with a primary discharge diagnosis of HF during 1998–2001.
Design
Observational.
Measurements of Evidence-Based Care
Pre-admission estimation of left ventricular ejection fraction (LVEF) for patients with known HF (n=494), in-hospital LVEF estimation for HF patients without known LVEF (n=452), and discharge prescriptions of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs-or-ARBs) to systolic HF (LVEF <45%) patients discharged alive who were eligible to receive those drugs (n=83). Eligibility for ACEIs-or-ARBs was defined as lack of prior allergy or adverse effect, serum creatinine <2.5 mg/dL, serum potassium <5.5 mEq/L, and systolic blood pressure >100 mm Hg.
Results
Pre-admission LVEF was estimated in 38% and 12% of patients receiving and not receiving cardiology consultation, respectively (adjusted odds ratio {AOR}, 3.49; 95% CI, 2.16–5.66; p <0.001). In-hospital LVEF was estimated in 71% and 28% of patients receiving and not receiving cardiology consultation, respectively (AOR, 6.01; 95% CI, 3.69–9.79; p <0.001). ACEIs-or-ARBs were prescribed to 62% and 82% of patients receiving and not receiving cardiology consultation, respectively (AOR, 0.24; 95% CI, 0.07–0.81; p=0.022).
Conclusion
In-hospital cardiology consultation was associated with significantly higher odds of LVEF estimation among NH residents with HF. However, it did not translate into higher odds of discharge prescriptions for ACEIs-or-ARBs to NH resident with systolic HF who were eligible for the receipt of these drugs.
doi:10.1016/j.jamda.2011.09.001
PMCID: PMC3750116  PMID: 21982687
heart failure; nursing home residents; cardiology consultation; evidence-based care
19.  Community-Based Care for the Specialized Management of Heart Failure 
Executive Summary
In August 2008, the Medical Advisory Secretariat (MAS) presented a vignette to the Ontario Health Technology Advisory Committee (OHTAC) on a proposed targeted health care delivery model for chronic care. The proposed model was defined as multidisciplinary, ambulatory, community-based care that bridged the gap between primary and tertiary care, and was intended for individuals with a chronic disease who were at risk of a hospital admission or emergency department visit. The goals of this care model were thought to include: the prevention of emergency department visits, a reduction in hospital admissions and re-admissions, facilitation of earlier hospital discharge, a reduction or delay in long-term care admissions, and an improvement in mortality and other disease-specific patient outcomes.
OHTAC approved the development of an evidence-based assessment to determine the effectiveness of specialized community based care for the management of heart failure, Type 2 diabetes and chronic wounds.
Please visit the Medical Advisory Secretariat Web site at: www.health.gov.on.ca/ohtas to review the following reports associated with the Specialized Multidisciplinary Community-Based care series.
Specialized multidisciplinary community-based care series: a summary of evidence-based analyses
Community-based care for the specialized management of heart failure: an evidence-based analysis
Community-based care for chronic wound management: an evidence-based analysis
Please note that the evidence-based analysis of specialized community-based care for the management of diabetes titled: “Community-based care for the management of type 2 diabetes: an evidence-based analysis” has been published as part of the Diabetes Strategy Evidence Platform at this URL: http://www.health.gov.on.ca/english/providers/program/mas/tech/ohtas/tech_diabetes_20091020.html
Please visit the Toronto Health Economics and Technology Assessment Collaborative Web site at: http://theta.utoronto.ca/papers/MAS_CHF_Clinics_Report.pdf to review the following economic project associated with this series:
Community-based Care for the specialized management of heart failure: a cost-effectiveness and budget impact analysis.
Objective
The objective of this evidence-based analysis was to determine the effectiveness of specialized multidisciplinary care in the management of heart failure (HF).
Clinical Need: Target Population and Condition
HF is a progressive, chronic condition in which the heart becomes unable to sufficiently pump blood throughout the body. There are several risk factors for developing the condition including hypertension, diabetes, obesity, previous myocardial infarction, and valvular heart disease.(1) Based on data from a 2005 study of the Canadian Community Health Survey (CCHS), the prevalence of congestive heart failure in Canada is approximately 1% of the population over the age of 12.(2) This figure rises sharply after the age of 45, with prevalence reports ranging from 2.2% to 12%.(3) Extrapolating this to the Ontario population, an estimated 98,000 residents in Ontario are believed to have HF.
Disease management programs are multidisciplinary approaches to care for chronic disease that coordinate comprehensive care strategies along the disease continuum and across healthcare delivery systems.(4) Evidence for the effectiveness of disease management programs for HF has been provided by seven systematic reviews completed between 2004 and 2007 (Table 1) with consistency of effect demonstrated across four main outcomes measures: all cause mortality and hospitalization, and heart-failure specific mortality and hospitalization. (4-10)
However, while disease management programs are multidisciplinary by definition, the published evidence lacks consistency and clarity as to the exact nature of each program and usual care comparators are generally ill defined. Consequently, the effectiveness of multidisciplinary care for the management of persons with HF is still uncertain. Therefore, MAS has completed a systematic review of specialized, multidisciplinary, community-based care disease management programs compared to a well-defined usual care group for persons with HF.
Evidence-Based Analysis Methods
Research Questions
What is the effectiveness of specialized, multidisciplinary, community-based care (SMCCC) compared with usual care for persons with HF?
Literature Search Strategy
A comprehensive literature search was completed of electronic databases including MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, Cochrane Library and Cumulative Index to Nursing & Allied Health Literature. Bibliographic references of selected studies were also searched. After a review of the title and abstracts, relevant studies were obtained and the full reports evaluated. All studies meeting explicit inclusion and exclusion criteria were retained. Where appropriate, a meta-analysis was undertaken to determine the pooled estimate of effect of specialized multidisciplinary community-based care for explicit outcomes. The quality of the body of evidence, defined as one or more relevant studies was determined using GRADE Working Group criteria. (11)
Inclusion Criteria
Randomized controlled trial
Systematic review with meta analysis
Population includes persons with New York Heart Association (NYHA) classification 1-IV HF
The intervention includes a team consisting of a nurse and physician one of which is a specialist in HF management.
The control group receives care by a single practitioner (e.g. primary care physician (PCP) or cardiologist)
The intervention begins after discharge from the hospital
The study reports 1-year outcomes
Exclusion Criteria
The intervention is delivered predominately through home-visits
Studies with mixed populations where discrete data for HF is not reported
Outcomes of Interest
All cause mortality
All cause hospitalization
HF specific mortality
HF specific hospitalization
All cause duration of hospital stay
HF specific duration of hospital stay
Emergency room visits
Quality of Life
Summary of Findings
One large and seven small randomized controlled trials were obtained from the literature search.
A meta-analysis was completed for four of the seven outcomes including:
All cause mortality
HF-specific mortality
All cause hospitalization
HF-specific hospitalization.
Where the pooled analysis was associated with significant heterogeneity, subgroup analyses were completed using two primary categories:
direct and indirect model of care; and
type of control group (PCP or cardiologist).
The direct model of care was a clinic-based multidisciplinary HF program and the indirect model of care was a physician supervised, nurse-led telephonic HF program.
All studies, except one, were completed in jurisdictions outside North America. (12-19) Similarly, all but one study had a sample size of less than 250. The mean age in the studies ranged from 65 to 77 years. Six of the studies(12;14-18) included populations with a NYHA classification of II-III. In two studies, the control treatment was a cardiologist (12;15) and two studies reported the inclusion of a dietitian, physiotherapist and psychologist as members of the multidisciplinary team (12;19).
All Cause Mortality
Eight studies reported all cause mortality (number of persons) at 1 year follow-up. (12-19) When the results of all eight studies were pooled, there was a statistically significant RRR of 29% with moderate heterogeneity (I2 of 38%). The results of the subgroup analyses indicated a significant RRR of 40% in all cause mortality when SMCCC is delivered through a direct team model (clinic) and a 35% RRR when SMCCC was compared with a primary care practitioner.
HF-Specific Mortality
Three studies reported HF-specific mortality (number of persons) at 1 year follow-up. (15;18;19) When the results of these were pooled, there was an insignificant RRR of 42% with high statistical heterogeneity (I2 of 60%). The GRADE quality of evidence is moderate for the pooled analysis of all studies.
All Cause Hospitalization
Seven studies reported all cause hospitalization at 1-year follow-up (13-15;17-19). When pooled, their results showed a statistically insignificant 12% increase in hospitalizations in the SMCCC group with high statistical heterogeneity (I2 of 81%). A significant RRR of 12% in all cause hospitalization in favour of the SMCCC care group was achieved when SMCCC was delivered using an indirect model (telephonic) with an associated (I2 of 0%). The Grade quality of evidence was found to be low for the pooled analysis of all studies and moderate for the subgroup analysis of the indirect team care model.
HF-Specific Hospitalization
Six studies reported HF-specific hospitalization at 1-year follow-up. (13-15;17;19) When pooled, the results of these studies showed an insignificant RRR of 14% with high statistical heterogeneity (I2 of 60%); however, the quality of evidence for the pooled analysis of was low.
Duration of Hospital Stay
Seven studies reported duration of hospital stay, four in terms of mean duration of stay in days (14;16;17;19) and three in terms of total hospital bed days (12;13;18). Most studies reported all cause duration of hospital stay while two also reported HF-specific duration of hospital stay. These data were not amenable to meta-analyses as standard deviations were not provided in the reports. However, in general (and in all but one study) it appears that persons receiving SMCCC had shorter hospital stays, whether measured as mean days in hospital or total hospital bed days.
Emergency Room Visits
Only one study reported emergency room visits. (14) This was presented as a composite of readmissions and ER visits, where the authors reported that 77% (59/76) of the SMCCC group and 84% (63/75) of the usual care group were either readmitted or had an ER visit within the 1 year of follow-up (P=0.029).
Quality of Life
Quality of life was reported in five studies using the Minnesota Living with HF Questionnaire (MLHFQ) (12-15;19) and in one study using the Nottingham Health Profile Questionnaire(16). The MLHFQ results are reported in our analysis. Two studies reported the mean score at 1 year follow-up, although did not provide the standard deviation of the mean in their report. One study reported the median and range scores at 1 year follow-up in each group. Two studies reported the change scores of the physical and emotional subscales of the MLHFQ of which only one study reported a statistically significant change from baseline to 1 year follow-up between treatment groups in favour of the SMCCC group in the physical sub-scale. A significant change in the emotional subscale scores from baseline to 1 year follow-up in the treatment groups was not reported in either study.
Conclusion
There is moderate quality evidence that SMCCC reduces all cause mortality by 29%. There is low quality evidence that SMCCC contributes to a shorter duration of hospital stay and improves quality of life compared to usual care. The evidence supports that SMCCC is effective when compared to usual care provided by either a primary care practitioner or a cardiologist. It does not, however, suggest an optimal model of care or discern what the effective program components are. A field evaluation could address this uncertainty.
PMCID: PMC3377506  PMID: 23074521
20.  The 2010 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To update the evidence-based recommendations for the prevention and treatment of hypertension in adults for 2010.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, randomized trials and systematic reviews of trials were preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the general lack of long-term morbidity and mortality data in this field. Progressive renal impairment was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease.
EVIDENCE:
A Cochrane Collaboration librarian conducted an independent MEDLINE search from 2008 to August 2009 to update the 2009 recommendations. To identify additional studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to 1500 mg (65 mmol) per day in adults 50 years of age or younger, to 1300 mg (57 mmol) per day in adults 51 to 70 years of age, and to 1200 mg (52 mmol) per day in adults older than 70 years of age; perform 30 min to 60 min of moderate aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week for men or nine standard drinks per week for women; follow a diet that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources, and that is low in saturated fat and cholesterol; and consider stress management in selected individuals with hypertension.
For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on the patient’s global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in patients with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, considerations for initial therapy should include thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. The combination of ACE inhibitors and ARBs should not be used, unless compelling indications are present to suggest consideration of dual therapy.
Agents appropriate for first-line therapy for isolated systolic hypertension include thiazide diuretics, long-acting dihydropyridine CCBs or ARBs. In patients with coronary artery disease, ACE inhibitors, ARBs or beta-blockers are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. In selected high-risk patients in whom combination therapy is being considered, an ACE inhibitor plus a long-acting dihydropyridine CCB is preferable to an ACE inhibitor plus a thiazide diuretic. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian lipid treatment guidelines. Selected patients with hypertension who do not achieve thresholds for statin therapy, but who are otherwise at high risk for cardiovascular events, should nonetheless receive statin therapy. Once blood pressure is controlled, low-dose acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to the strength of the evidence and voted on by the 63 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 80% consensus. These guidelines will continue to be updated annually.
SPONSORS:
The Canadian Hypertension Education Program process is sponsored by the Canadian Hypertension Society, Blood Pressure Canada, the Public Health Agency of Canada, the College of Family Physicians of Canada, the Canadian Pharmacists Association, the Canadian Council of Cardiovascular Nurses, and the Heart and Stroke Foundation of Canada.
PMCID: PMC2886555  PMID: 20485689
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
21.  Renin–angiotensin–aldosterone system blockade for cardiovascular diseases: current status 
British Journal of Pharmacology  2010;160(6):1273-1292.
Activation of the renin–angiotensin–aldosterone system (RAAS) results in vasoconstriction, muscular (vascular and cardiac) hypertrophy and fibrosis. Established arterial stiffness and cardiac dysfunction are key factors contributing to subsequent cardiovascular and renal complications. Blockade of RAAS has been shown to be beneficial in patients with hypertension, acute myocardial infarction, chronic systolic heart failure, stroke and diabetic renal disease. An aggressive approach for more extensive RAAS blockade with combination of two commonly used RAAS blockers [ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)] yielded conflicting results in different patient populations. Combination therapy is also associated with more side effects, in particular hypotension, hyperkalaemia and renal impairment. Recently published ONTARGET study showed ACEI/ARB combination therapy was associated with more adverse effects without any increase in benefit. The Canadian Hypertension Education Program responded with a new warning: ‘Do not use ACEI and ARB in combination’. However, the European Society of Cardiology in their updated heart failure treatment guidelines still recommended ACEI/ARB combo as a viable option. This apparent inconsistency among guidelines generates debate as to which approach of RAAS inhibition is the best. The current paper reviews the latest evidence of isolated ACEI or ARB use and their combination in cardiovascular diseases, and makes recommendations for their prescriptions in specific patient populations.
doi:10.1111/j.1476-5381.2010.00750.x
PMCID: PMC2938800  PMID: 20590619
renin–angiotensin–aldosterone system; angiotensin converting enzyme inhibitors; angiotensin II type 1 receptor blockers; hypertension; myocardial infarction; heart failure; stroke; diabetic nephropathy
22.  Angiotensin II type 1 receptor blockers as a first choice in patients with acute myocardial infarction 
Background/Aims:
Angiotensin II type 1 receptor blockers (ARBs) have not been adequately evaluated in patients without left ventricular (LV) dysfunction or heart failure after acute myocardial infarction (AMI).
Methods:
Between November 2005 and January 2008, 6,781 patients who were not receiving angiotensin-converting enzyme inhibitors (ACEIs) or ARBs were selected from the Korean AMI Registry. The primary endpoints were 12-month major adverse cardiac events (MACEs) including death and recurrent AMI.
Results:
Seventy percent of the patients were Killip class 1 and had a LV ejection fraction ≥ 40%. The prescription rate of ARBs was 12.2%. For each patient, a propensity score, indicating the likelihood of using ARBs during hospitalization or at discharge, was calculated using a non-parsimonious multivariable logistic regression model, and was used to match the patients 1:4, yielding 715 ARB users versus 2,860 ACEI users. The effect of ARBs on in-hospital mortality and 12-month MACE occurrence was assessed using matched logistic and Cox regression models. Compared with ACEIs, ARBs significantly reduced in-hospital mortality(1.3% vs. 3.3%; hazard ratio [HR], 0.379; 95% confidence interval [CI], 0.190 to0.756; p = 0.006) and 12-month MACE occurrence (4.6% vs. 6.9%; HR, 0.661; 95% CI, 0.457 to 0.956; p = 0.028). However, the benefit of ARBs on 12-month mortality compared with ACEIs was marginal (4.3% vs. 6.2%; HR, 0.684; 95% CI, 0.467 to 1.002; p = 0.051).
Conclusions:
Our results suggest that ARBs are not inferior to, and may actually be better than ACEIs in Korean patients with AMI.
doi:10.3904/kjim.2014.268
PMCID: PMC4773713  PMID: 26701233
Angiotensin-converting enzyme inhibitors; Angiotensin II type 1 receptor blockers; Myocardial infarction; Mortality; Secondary prevention
23.  Angiotensin receptor blockers and outcomes in real-world older patients with heart failure and preserved ejection fraction: a propensity-matched inception cohort clinical effectiveness study 
European Journal of Heart Failure  2012;14(10):1179-1188.
Aims
To examine the clinical effectiveness of angiotensin receptor blockers (ARBs) in older patients with heart failure and preserved ejection fraction (HF-PEF).
Methods and results
Of the 10 570 hospitalized HF-PEF patients, aged ≥65 years, EF ≥40%, in OPTIMIZE-HF (2003–2004), linked to Medicare data (up to 31 December 2008), 3806 were not receiving angiotensin-converting enzyme inhibitors or prior ARB therapy. Of these, 303 (8%) patients received new discharge prescriptions for ARBs. Propensity scores for the receipt of ARBs, estimated for each of the 3806 patients, were used to assemble a cohort of 296 pairs of patients receiving and not receiving ARBs, who were balanced on 114 baseline characteristics. Patients had a mean age of 80 years, mean EF of 55%, 69% were women, and 12% were African American. During 6 years of follow-up, the primary composite endpoint of all-cause mortality or HF hospitalization occurred in 79% (235/296) and 81% (241/296) of patients receiving and not receiving ARBs, respectively [hazard ratio (HR) associated with ARB use 0.88, 95% confidence interval (CI) 0.74–1.06; P = 0.179]. ARB use had no association with individual endpoints of all-cause mortality (HR 0.93, 95% CI 0.76–1.14; P = 0.509), HF hospitalization (HR 0.90, 95% CI, 0.72–1.14; P = 0.389), or all-cause hospitalization (HR 0.91, 95% CI 0.77–1.08; P = 0.265). These associations remained unchanged when we compared any (prevalent and new prescriptions) ARB use vs. non-use in a separately assembled propensity-matched cohort of 1137 pairs of HF-PEF patients.
Conclusions
In real-world older HF-PEF patients, ARB use was not associated with improved clinical outcomes.
doi:10.1093/eurjhf/hfs101
PMCID: PMC3448391  PMID: 22759445
Angiotensin receptor blockers; Heart failure; Preserved ejection fraction
24.  Baseline predictors of tolerability to carvedilol in patients with chronic heart failure 
Heart  2000;84(6):615-619.
OBJECTIVE—To determine baseline predictors of tolerance to the α/β blocker carvedilol in everyday clinical practice.
DESIGN—Retrospective analysis of tolerance to carvedilol in patients with chronic heart failure. Tolerance was defined as currently on carvedilol or on it at the time of death or heart transplantation. To meet the criteria for tolerance, carvedilol had to be prescribed at a stable dose for ⩾ 3 months.
SETTING—Everyday clinical practice, comprising both hospital specialist practice and private practice. Tolerance was assessed in all patients prescribed carvedilol for chronic heart failure in those practices.
PATIENTS—808 consecutive patients in both hospital specialist (611 patients) and private practice (197 patients).
MAIN OUTCOME MEASURES—Baseline predictors of tolerance assessed by proportional hazards analysis. Both univariate and multivariate analyses were performed.
RESULTS—Within the entire cohort of 808 patients, 95 had stopped carvedilol, 606 were currently receiving the drug, 50 had died, and 44 had received a heart transplant. Overall, 88% of patients tolerated carvedilol (87% in the hospital specialist group, 92% in the private practitioner group). Factors that indicated impaired tolerance by univariate analysis were increased age in years (hazard ratio 1.01, 95% confidence interval (CI) 1.0 to 1.3), low diastolic blood pressure (hazard ratio 1.04, 95% CI 1.02 to 1.08), and raised plasma urea concentration (hazard ratio 1.04, 95% CI 1.02 to 1.05). New York Heart Association (NYHA) class was also a marker of tolerance (proportion not tolerated: 3% class I; 9% class II; 13% class III, 22% class IV). By multivariate analysis, no single baseline variable was an independent marker of inability to tolerate carvedilol. Tolerance was also assessed in relation to traditional precautions or relative contraindications to β blockade. Tolerance in these subgroups was: chronic obstructive airways disease/asthma 85% (89 patients), diabetes 86% (127 patients), peripheral vascular disease 84% (58 patients), concomitant amiodarone treatment 83% (230 patients), and heart rate < 70 beats/min 84% (184 patients).
CONCLUSIONS—β Blocker treatment was well tolerated in everyday clinical practice, including non-hospital-based private practice. There was no single predictor of poor tolerance on multivariate analysis, although there was a clear association with NYHA class as well as age, diastolic blood pressure, and plasma urea on univariate analysis. Carvedilol was tolerated well among selected patients with traditional contraindications to β blockade in this situation.


Keywords: chronic heart failure; β blockade; carvedilol
doi:10.1136/heart.84.6.615
PMCID: PMC1729537  PMID: 11083738
25.  Cardiovascular disease treatment among patients with severe mental illness: a data linkage study between primary and secondary care 
The British Journal of General Practice  2016;66(647):e374-e381.
Background
Suboptimal treatment of cardiovascular diseases (CVD) among patients with severe mental illness (SMI) may contribute to physical health disparities.
Aim
To identify SMI characteristics associated with meeting CVD treatment and prevention guidelines.
Design and setting
Population-based electronic health record database linkage between primary care and the sole provider of secondary mental health care services in south east London, UK.
Method
Cardiovascular disease prevalence, risk factor recording, and Quality and Outcomes Framework (QOF) clinical target achievement were compared among 4056 primary care patients with SMI whose records were linked to secondary healthcare records and 270 669 patients without SMI who were not known to secondary care psychiatric services, using multivariate logistic regression modelling. Data available from secondary care records were then used to identify SMI characteristics associated with QOF clinical target achievement.
Results
Patients with SMI and with coronary heart disease and heart failure experienced reduced prescribing of beta blockers and angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACEI/ARB). A diagnosis of schizophrenia, being identified with any indicator of risk or illness severity, and being prescribed with depot injectable antipsychotic medication was associated with the lowest likelihood of prescribing.
Conclusion
Linking primary and secondary care data allows the identification of patients with SMI most at risk of undertreatment for physical health problems.
doi:10.3399/bjgp16X685189
PMCID: PMC4871302  PMID: 27114210
cardiovascular diseases; data linkage; health inequalities; primary health care; psychoses

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