Gordon T. McInnes

Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial

BACKGROUND The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic. METHODS Of 19342 hypertensive patients (aged 40-79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat. FINDINGS Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56-0.96], p=0.024), total cardiovascular events (389 vs 486, 0.79 [0.69-0.90], p=0.0005), and total coronary events (178 vs 247, 0.71 [0.59-0.86], p=0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71-1.06], p=0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up. INTERPRETATION The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.

Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial

BACKGROUND The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk. METHODS 15?245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomised, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint, defined as a composite of cardiac mortality and morbidity. Patients from 31 countries were followed up for a mean of 4.2 years. FINDINGS Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period (blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month; 1.5/1.3 mm Hg after 1 year; p<0.001 between groups). The primary composite endpoint occurred in 810 patients in the valsartan group (10.6%, 25.5 per 1000 patient-years) and 789 in the amlodipine group (10.4%, 24.7 per 1000 patient-years; hazard ratio 1.04, 95% CI 0.94-1.15, p=0.49). INTERPRETATION The main outcome of cardiac disease did not differ between the treatment groups. Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes. The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk.

Prevention of Coronary and Stroke Events with Atorvastatin in Hypertensive Patients who have Average or Lower-than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial— Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial

SummaryBackground The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic. Methods Of 19 342 hypertensive patients (aged 40–79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10 305 with nonfasting total cholesterol concentrations 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat. Findings Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50–0.83], p = 0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56–0.96], p = 0.024), total cardiovascular events (389 vs 486, 0.79 [0.69–0.90], p = 0.0005), and total coronary events (178 vs 247, 0.71 [0.59–0.86], p = 0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71–1.06], p = 0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up. Interpretation The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.

Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV.

Summary of recommendationsProvide advice on life-style modifications for all people with high blood pressure (BP) and those with borderline or high-normal BP. Advice on effective nonpharmacological interventions is provided (A).Initiate antihypertensive drug therapy in people with sustained systolic BP (SBP) ⩾160 mmHg or sustained diastolic BP (DBP) ⩾100 mmHg (A).Make treatment decisions in people with sustained SBP between 140 and 159 mmHg and/or sustained DBP between 90 and 99 mmHg according to the presence or absence of cardiovascular disease, other target organ damage, or an estimated cardiovascular disease (CVD) risk of ⩾20% over 10 years, according to the Joint British Societies CVD risk assessment programme/risk chart (A).CVD risk replaces CHD risk estimation to reflect the importance of stroke prevention as well as CHD prevention. The new CVD risk threshold of ⩾20% is equivalent to a CHD risk of approximately ⩾15% over 10 years.In people with diabetes mellitus, initiate antihypertensive drug therapy if SBP is sustained ⩾140 mmHg and/or DBP is sustained ⩾90 mmHg (B).In nondiabetic people with hypertension, the optimal BP treatment goals are: SBP <140 mmHg and DBP <85 mmHg. The minimum acceptable level of control (Audit Standard) recommended is <150/<90 mmHg. Despite the best practice, these levels will be difficult to achieve in some hypertensive people (B).In people with diabetes and high BP, optimal BP goals are: SBP <130 mmHg and DBP <80 mmHg. The minimum acceptable level of control (Audit Standard) recommended is <140/<80 mmHg. Despite the best practice, these levels will be difficult to achieve in some people with diabetes and hypertension (B).Meta-analyses of BP-lowering trials have confirmed that, in general, the main determinant of benefit from BP-lowering drugs is the achieved BP, rather than choice of therapy. In some circumstances, there are compelling indications and contraindications for specific classes of antihypertensive drugs, and these are specified (A).Most people with high BP will require at least two BP-lowering drugs to achieve the recommended BP goals. A treatment algorithm (AB/CD) is provided to advise on the sequencing of drugs and logical drug combinations (C). When there are no cost disadvantages, fixed drug combinations are recommended to reduce the number of medications, which may enhance adherence to treatment (C).Other drugs that reduce CVD risk must also be considered, notably, low-dose aspirin and statin therapy (A).Unless contraindicated, low-dose aspirin (75 mg/day) is recommended for all people needing secondary prevention of ischaemic CVD, and primary prevention in people with hypertension over the age of 50 years who have a 10-year CVD risk ⩾20% and in whom BP is controlled to the audit standard (A).Statin therapy is recommended for all people with high BP complicated by CVD, irrespective of baseline total cholesterol or low-density lipoprotein (LDL)-cholesterol levels. Similarly, statin therapy is also recommended for primary prevention in people with high BP who have a 10-year CVD risk ⩾20%, estimated from the Joint British Societies CVD risk-assessment programme/chart. Optimal cholesterol lowering should reduce the total cholesterol by 25% or LDL-cholesterol by 30% or achieve a total cholesterol of <4.0 mmol/l or LDL-cholesterol of <2.0 mmol/l, whichever is the greatest reduction (A).Glycaemic control should be optimised in people with diabetes, for example, HbA1c <7% (A).Advice is provided on the clinical management of hypertension in specific patient groups, that is, the elderly, ethnic minorities, people with diabetes mellitus, chronic renal disease, and in women (pregnancy, oral contraceptive use and hormone-replacement therapy).Suggestions for the improved implementation and audit of these guidelines in primary care are provided.

British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary

Much new evidence has emerged on the importance of blood pressure as a risk factor for cardiovascular disease; the importance of lifestyle measures for the prevention and treatment of hypertension; the efficacy and safety of different drug classes; management of hypertension in groups at higher risk, including people with diabetes; the importance of assessing the total risk of cardiovascular disease; and additional benefits associated with the use of statins. Concern remains that national surveys continue to show substantial underdiagnosis, undertreatment, and poor rates of blood pressure control in the United Kingdom.1 A key reason for this is the predominant use of monotherapy by most doctors.1 To improve this suboptimal treatment, the British Hypertension Society recommends a treatment algorithm based on the AB/CD rule.2 Treatment of blood pressure alone will leave many hypertensive patients at unacceptably high risk of cardiovascular complications and death. This guideline reinforces the view that doctors should not focus solely on blood pressure but must also formally assess total risk of cardiovascular disease and use multifactorial interventions, including statins and aspirin, to reduce it. Most management of blood pressure and risk of cardiovascular disease will take place in primary care, and these guidelines are intended for general practitioners, practice nurses, and generalists in hospital practice. Detailed advice on implementation and the implications of the national service frameworks and the general medical services contract are contained in the full document (http://www.bhsoc.org/).3 These guidelines have been prepared by the guidelines working party of the British Hypertension Society on behalf of the society. The working party reviewed new data that have become available since the previous guidelines were published4 and amended the recommendations accordingly. Drafts of the full document were improved by consultation with …

Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test whether, for the same achieved blood pressures, regimens based on valsartan or amlodipine would have differing effects on cardiovascular endpoints in high risk hypertension. But inequalities in blood pressure, favouring amlodipine, throughout the multiyear trial precluded comparison of outcomes. A technique of serial median matching, applied at 6 months when treatment adjustments intended to achieve control of blood pressure were complete, created 5006 valsartan-amlodipine patient pairs matched exactly for systolic blood pressure, age, sex, and the presence or absence of previous coronary disease, stroke, or diabetes. Subsequent combined cardiac events, myocardial infarction, stroke, and mortality were almost identical in the two cohorts, but admission to hospital for heart failure was significantly lower with valsartan. Reaching blood pressure control (systolic <140 mm Hg) by 6 months, independent of drug type, was associated with significant benefits for subsequent major outcomes; the blood pressure response after just 1 month of treatment predicted events and survival.

Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)

BACKGROUND Results of the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) show significantly lower rates of coronary and stroke events in individuals allocated an amlodipine-based combination drug regimen than in those allocated an atenolol-based combination drug regimen (HR 0.86 and 0.77, respectively). Our aim was to assess to what extent these differences were due to significant differences in blood pressures and in other variables noted after randomisation. METHODS We used data from ASCOT-BPLA (n=19 257) and compared differences in accumulated mean blood pressure levels at sequential times in the trial with sequential differences in coronary and stroke events. Serial mean matching for differences in systolic blood pressure was used to adjust HRs for differences in these events. We used an updated Cox-regression model to assess the effects of differences in accumulated mean levels of various measures of blood pressure, serum HDL-cholesterol, triglycerides and potassium, fasting blood glucose, heart rate, and bodyweight on differences in event rates. FINDINGS We noted no temporal link between size of differences in blood pressure and different event rates. Serial mean matching for differences in systolic blood-pressure attenuated HRs for coronary and stroke events to a similar extent as did adjustments for systolic blood-pressure differences in Cox-regression analyses. HRs for coronary events and stroke adjusted for blood pressure rose from 0.86 (0.77-0.96) to 0.88 (0.79-0.98) and from 0.77 (0.66-0.89) to 0.83 (0.72-0.96), respectively. Multivariate adjustment gave HRs of 0.94 (0.81-1.08) for coronary events (HDL cholesterol being the largest contributor) and 0.87 (0.73-1.05) for stroke events. INTERPRETATION Multivariate adjustment accounted for about half of the differences in coronary events and for about 40% of the differences in stroke events between the treatment regimens tested in ASCOT-BPLA, but residual differences were no longer significant. These residual differences could indicate inadequate statistical adjustment, but it remains possible that differential effects of the two treatment regimens on other variables also contributed to the different rates noted, particularly for stroke.

Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial

Summary Background Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure. Methods In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18–79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25–50 mg), bisoprolol (5–10 mg), doxazosin modified release (4–8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. Findings Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (–8·70 mm Hg [95% CI −9·72 to −7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; −4·26 [–5·13 to −3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (–4·03 [–5·04 to −3·02]; p<0·0001) and versus bisoprolol (–4·48 [–5·50 to −3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion. Interpretation Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. Funding The British Heart Foundation and National Institute for Health Research.

Rationale, design, methods and baseline demography of participants of the Anglo-scandinavian Cardiac Outcomes Trial

Objective To test the primary hypothesis that a newer antihypertensive treatment regimen (calcium channel blocker ± an angiotensin converting enzyme inhibitor) is more effective than an older regimen (β-blocker ± a diuretic) in the primary prevention of coronary heart disease (CHD). To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterol ⩽ 6.5 mmol/l. Design Prospective, randomized, open, blinded endpoint trial with a double-blinded 2 × 2 factorial component. Setting Patients were recruited mainly from general practices. Patients Men and women aged 40–79 were eligible if their blood pressure was ⩾160 mmHg systolic or ⩾ 100 mmHg diastolic (untreated) or ⩾140 mmHg systolic or ⩾ 90 mmHg diastolic (treated) at randomization. Interventions Patients received either amlodipine (5/10 mg) ± perindopril (4/8 mg) or atenolol (50/100 mg) ± bendroflumethiazide (1.25/2.5 mg) +K+ with further therapy as required to reach a blood pressure of ⩽140 mmHg systolic and 90 mmHg diastolic. Patients with a total cholesterol of ⩽ 6.5 mmol/l were further randomized to receive either atorvastatin 10 mg or placebo daily. Main outcome measure Non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD). Results 19 342 men and women were initially randomized, of these 10 297 were also randomized into the lipid-lowering limb. All patients had three or more additional cardiovascular risk factors. Conclusions The study has 80% power (at the 5% level) to detect a relative difference of 20% in CHD endpoints between the calcium channel blocker-based regimen and the β-blocker-based regimen. The lipid-lowering limb of the study has 90% power at the 1% level to detect a relative difference of 30% in CHD endpoints between groups.

Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: The VALUE trial

Background Atrial fibrillation (AF) is the most common arrhythmia and increases cardiovascular risk in hypertensive patients. Therefore, in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) a prespecified objective was to compare the effects of valsartan and amlodipine on new-onset AF. Methods A total of 15 245 hypertensive patients at high cardiovascular risk received valsartan 80–160 mg/day or amlodipine 5–10 mg/day combined with additional antihypertensive agents. Electrocardiograms were obtained every year and analyzed centrally for evidence of left ventricular hypertrophy and new-onset AF. Results At baseline, AF was diagnosed in 2.6% of 7649 valsartan recipients and 2.6% of 7596 amlodipine recipients. During antihypertensive treatment the incidence of at least one documented occurrence of new-onset AF was 3.67% with valsartan and 4.34% with amlodipine {unadjusted hazard ratio 0.843, [95% confidence interval (CI): 0.713, 0.997], P = 0.0455}. The incidence of persistent AF was 1.35% with valsartan and 1.97% with amlodipine [unadjusted hazard ratio 0.683 (95% CI: 0.525, 0.889), P = 0.0046]. Conclusions Valsartan-based treatment reduced the development of new-onset AF, particularly sustained AF in hypertensive patients, compared with amlodipine-based therapy. These findings suggest that angiotensin II receptor blockers may result in greater benefits than calcium antagonists in hypertensive patients at risk of new-onset AF.