Daniel G. Hackam

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/m(2) to 24.9 kg/m(2)) 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 patients 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.

The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2013. This years update includes 2 new recommendations. First, among nonhypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise does not adversely influence blood pressure (BP) (Grade D). Thus, such patients need not avoid this type of exercise for fear of increasing BP. Second, and separately, for very elderly patients with isolated systolic hypertension (age 80 years or older), the target for systolic BP should be < 150 mm Hg (Grade C) rather than < 140 mm Hg as recommended for younger patients. We also discuss 2 additional topics at length (the pharmacological treatment of mild hypertension and the possibility of a diastolic J curve in hypertensive patients with coronary artery disease). In light of several methodological limitations, a recent systematic review of 4 trials in patients with stage 1 uncomplicated hypertension did not lead to changes in management recommendations. In addition, because of a lack of prospective randomized data assessing diastolic BP thresholds in patients with coronary artery disease and hypertension, no recommendation to set a selective diastolic cut point for such patients could be affirmed. However, both of these issues will be examined on an ongoing basis, in particular as new evidence emerges.

Carotid Plaque Area A Tool for Targeting and Evaluating Vascular Preventive Therapy

Background and Purpose— Carotid plaque area measured by ultrasound (cross-sectional area of longitudinal views of all plaques seen) was studied as a way of identifying patients at increased risk of stroke, myocardial infarction, and vascular death. Methods— Patients from an atherosclerosis prevention clinic were followed up annually for up to 5 years (mean, 2.5±1.3 years) with baseline and follow-up measurements recorded. Plaque area progression (or regression) was defined as an increase (or decrease) of ≥0.05 cm2 from baseline. Results— Carotid plaque areas from 1686 patients were categorized into 4 quartile ranges: 0.00 to 0.11 cm2 (n=422), 0.12 to 0.45 cm2 (n=424), 0.46 to 1.18 cm2 (n=421), and 1.19 to 6.73 cm2 (n=419). The combined 5-year risk of stroke, myocardial infarction, and vascular death increased by quartile of plaque area: 5.6%, 10.7%, 13.9%, and 19.5%, respectively (P <0.001) after adjustment for all baseline patient characteristics. A total of 1085 patients had ≥1 annual carotid plaque area measurements: 685 (63.1%) had carotid plaque progression, 306 (28.2%) had plaque regression, and 176 (16.2%) had no change in carotid plaque area over the period of follow-up. The 5-year adjusted risk of combined outcome was 9.4%, 7.6%, and 15.7% for patients with carotid plaque area regression, no change, and progression, respectively (P =0.003). Conclusions— Carotid plaque area and progression of plaque identified high-risk patients. Plaque measurement may be useful for targeting preventive therapy and evaluating new treatments and response to therapy and may improve cost-effectiveness of secondary preventive treatment.

Shift work and vascular events: systematic review and meta-analysis

Objective To synthesise the association of shift work with major vascular events as reported in the literature. Data sources Systematic searches of major bibliographic databases, contact with experts in the field, and review of reference lists of primary articles, review papers, and guidelines. Study selection Observational studies that reported risk ratios for vascular morbidity, vascular mortality, or all cause mortality in relation to shift work were included; control groups could be non-shift (“day”) workers or the general population. Data extraction Study quality was assessed with the Downs and Black scale for observational studies. The three primary outcomes were myocardial infarction, ischaemic stroke, and any coronary event. Heterogeneity was measured with the I2 statistic and computed random effects models. Results 34 studies in 2 011 935 people were identified. Shift work was associated with myocardial infarction (risk ratio 1.23, 95% confidence interval 1.15 to 1.31; I2=0) and ischaemic stroke (1.05, 1.01 to 1.09; I2=0). Coronary events were also increased (risk ratio 1.24, 1.10 to 1.39), albeit with significant heterogeneity across studies (I2=85%). Pooled risk ratios were significant for both unadjusted analyses and analyses adjusted for risk factors. All shift work schedules with the exception of evening shifts were associated with a statistically higher risk of coronary events. Shift work was not associated with increased rates of mortality (whether vascular cause specific or overall). Presence or absence of adjustment for smoking and socioeconomic status was not a source of heterogeneity in the primary studies. 6598 myocardial infarctions, 17 359 coronary events, and 1854 ischaemic strokes occurred. On the basis of the Canadian prevalence of shift work of 32.8%, the population attributable risks related to shift work were 7.0% for myocardial infarction, 7.3% for all coronary events, and 1.6% for ischaemic stroke. Conclusions Shift work is associated with vascular events, which may have implications for public policy and occupational medicine.

Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis

BACKGROUND Atherosclerosis and sepsis share several pathophysiological similarities, including immune dysregulation, increased thrombogenesis, and systemic inflammation. The relation between statins and risk of sepsis in patients with atherosclerosis is unknown. METHODS We did a population-based cohort analysis through linked administrative databases in Ontario, Canada, with accrual from 1997 to 2002. We identified 141,487 patients older than 65 years who had been hospitalised for an acute coronary syndrome, ischaemic stroke, or revascularisation, who survived for at least 3 months after discharge. 46,662 (33%) were prescribed a statin within 90 days of discharge, 94,825 (67%) were not. Propensity-based matching, which accounted for each individuals likelihood of receiving a statin, yielded a cohort of 69,168 patients, of whom half (34,584) received a statin and half (34,584) did not. FINDINGS Incidence of sepsis was lower in patients receiving statins than in controls (71.2 vs 88.0 events per 10,000 person-years; hazard ratio [HR] 0.81; 95% CI 0.72-0.91). Adjustment for demographic characteristics, sepsis risk factors, comorbidities, and health-care use gave similar results (HR 0.81; 95% CI 0.72-0.90). The protective association between statins and sepsis persisted in high-risk subgroups, including patients with diabetes mellitus, chronic renal failure, or a history of infections. Significant reductions in severe sepsis (HR 0.83; 95% CI 0.70-0.97) and fatal sepsis (0.75; 0.61-0.93) were also observed. No benefit was noted with non-statin lipid-lowering agents (0.95; 0.75-1.22). IMPLICATIONS Use of statins in patients with atherosclerosis is associated with a reduced risk of subsequent sepsis. Randomised trials of statins for prevention of sepsis are warranted.

Effects of Intensive Medical Therapy on Microemboli and Cardiovascular Risk in Asymptomatic Carotid Stenosis

OBJECTIVE To assess the effect of more intensive medical therapy on the rate of transcranial Doppler (TCD) microemboli and cardiovascular events in patients with asymptomatic carotid stenosis (ACS). DESIGN A prospective study. SETTING A teaching hospital. PATIENTS Four hundred sixty-eight patients with ACS greater than 60% by Doppler peak velocity. MAIN OUTCOME MEASURES We compared (1) the proportion of ACS patients who had microemboli on TCD, (2) cardiovascular events, (3) rate of carotid plaque progression, and (4) baseline medical therapy, before and since 2003. RESULTS Among 468 ACS patients, 199 were enrolled between January 1, 2000, and December 31, 2002; and 269 were enrolled between January 1, 2003, and July 30, 2007. Microemboli were present in 12.6% before 2003 and 3.7% since 2003 (P < .001). The decline in microemboli coincided with better control of plasma lipids and slower progression of carotid total plaque area. Since 2003, there have been significantly fewer cardiovascular events among patients with ACS: 17.6% had stroke, death, myocardial infarction, or carotid endarterectomy for symptoms before 2003, vs 5.6% since 2003 (P < .001). The rate of carotid plaque progression in the first year of follow-up has declined from 69 mm(2) (SD, 96 mm(2)) to 23 mm(2) (SD, 86 mm(2)) (P < .001). CONCLUSIONS Cardiovascular events and microemboli on TCD have markedly declined with more intensive medical therapy. Less than 5% of patients with ACS now stand to benefit from revascularization; patients with ACS should receive intensive medical therapy and should only be considered for revascularization if they have microemboli on TCD.

The 2011 Canadian Hypertension Education Program Recommendations for the Management of Hypertension: Blood Pressure Measurement, Diagnosis, Assessment of Risk, and Therapy

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are: (1) a recommendation was made for using comparative risk analogies when communicating a patients cardiovascular risk; (2) diagnostic testing issues for renal artery stenosis were discussed; (3) recommendations were added for the management of hypertension during the acute phase of stroke; (4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors; (5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer.

Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case-control study.

BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors prevent the expansion and rupture of aortic aneurysms in animals. We investigated the association between ACE inhibitors and rupture in patients with abdominal aortic aneurysms. METHODS We did a population-based case-control study of linked administrative databases in Ontario, Canada. The sample included consecutive patients older than 65 (n=15,326) admitted to hospital with a primary diagnosis of ruptured or intact abdominal aortic aneurysm between April 1, 1992, and April 1, 2002. FINDINGS Patients who received ACE inhibitors before admission were significantly less likely to present with ruptured aneurysm (odds ratio [OR] 0.82, 95% CI 0.74-0.90) than those who did not receive ACE inhibitors. Adjustment for demographic characteristics, risk factors for rupture, comorbidities, contraindications to ACE inhibitors, measures of health-care use, and aneurysm screening yielded similar results (0.83, 0.73-0.95). Consistent findings were noted in subgroups at high risk of rupture, including patients older than 75 years and those with a history of hypertension. Conversely, such protective associations were not observed for beta blockers (1.02, 0.89-1.17), calcium channel blockers (1.01, 0.89-1.14), alpha blockers (1.15, 0.86-1.54), angiotensin receptor blockers (1.24, 0.71-2.18), or thiazide diuretics (0.91, 0.78-1.07). INTERPRETATION ACE inhibitors are associated with a reduced risk of ruptured abdominal aortic aneurysm, unlike other antihypertensive agents. Randomised trials of ACE inhibitors for prevention of aortic rupture might be warranted.

Statins and sepsis: multiple modifications at multiple levels

Sepsis, an infection-induced inflammatory syndrome, is a leading and increasing cause of mortality worldwide. Animal and human observational studies suggest statins may prevent the morbidity and mortality associated with the sepsis syndrome. In this Review, we describe the demonstrated mechanisms through which statins modulate the inflammatory response associated with sepsis. These mechanisms include effects on cell signalling with consequent changes at the transcriptional level, the induction of haem oxygenase, the direct alteration of leucocyte-endothelial cell interaction, and the reduced expression of MHC II. Since statins do not target individual inflammatory mediators, but possibly reduce the overall magnitude of the systemic response, this effect could prove an important distinguishing feature modulating the host response to septic insults. This work establishes the biological plausibility needed for future trials of statins in critical illness.

Combining Multiple Approaches for the Secondary Prevention of Vascular Events After Stroke: A Quantitative Modeling Study

Background and Purpose— Numerous effective strategies for the secondary prevention of cardiovascular events in high-risk patients have now been established. We sought to calculate the cumulative benefit of combining multiple strategies for preventing recurrent events in patients with a history of ischemic stroke or transient ischemic attack. Methods— A comprehensive literature search was undertaken to identify meta-analyses of randomized controlled trials reporting on the efficacy of secondary prevention strategies. The baseline incidence of vascular events was modeled from the Life Long After Cerebral Ischemia study. Strategies were combined on a multiplicative scale and cumulative risk reductions were computed over a 5-year interval. Results— The combination of 5 proven strategies applied to survivors of an initial stroke or transient ischemic attack—dietary modification, exercise, aspirin, a statin, and an antihypertensive agent—could result in a cumulative relative risk reduction of 80%. Given a 5-year major cardiovascular event rate of 24%, this translates to a number needed to treat of about 5. Further gains would result from applying multimodality therapy over longer intervals and enriching the base strategy with dual antiplatelet therapy, high-dose statins, and more intensive blood pressure–lowering. Even more benefit would be present in high-risk subgroups with the addition, where appropriate, of carotid endarterectomy, moderate intensity oral anticoagulants, glycemic control, and smoking cessation. Conclusions— At least four-fifths of recurrent vascular events in patients with cerebrovascular disease might be prevented by application of a comprehensive, multifactorial approach.