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The management of hypertension in ischaemic heart disease |
Purpose of review: Patients with hypertension and coronary artery disease are often inadequately treated. Blood pressure levels remain unacceptably high in about half of such patients. A significant shortfall exists between guidelines and practice in implementing evidence-based drug therapy.
Recent findings: Recent trials underscore the importance of blood pressure reduction. The purported superiority of specific drug classes, notably angiotensin-converting enzyme inhibitors and [beta]-blockers, is increasingly debated. Conversely, the benefits of calcium channel blockers are increasingly recognized. Irrespective of differences, all three agents are frequently required to achieve blood pressure targets. Beyond blood pressure reduction, statin therapy is undoubtedly the single most important risk factor intervention. New studies suggest that intensive lipid lowering and greater reductions in low-density lipoprotein cholesterol will further reduce major cardiovascular events. Finally, the impact of smoking cessation, exercise, and diet is often underestimated.
Summary: The prognosis for patients is critically dependent on reducing global cardiovascular risk by addressing all modifiable risk factors. The cornerstone of treatment remains blood pressure reduction, using agents with both antihypertensive and antianginal properties.
Abbreviations ACE: angiotensin-converting enzyme; CAD: coronary artery disease; CAMELOT: Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis trial; EUROPA: European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease; HOPE: Heart Outcomes Prevention Evaluation study; LDL-c: low-density lipoprotein cholesterol; TNT: Treating to New Targets trial.
Patients with hypertension are at an increased risk of myocardial ischaemia through several mechanisms and in particular through the coexistence of left ventricular hypertrophy and coronary artery disease (CAD). Angina, myocardial infarction, left ventricular dysfunction, and sudden death are the principal clinical expressions of CAD. Left ventricular hypertrophy may itself cause angina and substantially increases risk of sudden death. In both situations myocardial ischaemia may also be asymptomatic. This article focuses principally on the management of hypertension in patients with ischaemic heart disease secondary to obstructive CAD. Blood pressure levels remain unacceptably high in about half of such patients in Europe [1]. An understanding of the pathophysiology of myocardial ischaemia facilitates better decision making regarding choice of antihypertensive therapy.
There is a sound pathophysiological basis for reducing blood pressure in hypertensive patients with ischaemic heart disease. Both elevated systolic blood pressure and left ventricular hypertrophy have a detrimental effect on myocardial oxygen requirements. Effective blood pressure control and regression of hypertrophy will lessen the imbalance between myocardial supply and demand. An ideal therapeutic regimen would combine drugs that optimize the supply-and-demand relationship with drugs that reduce cardiovascular events (Table 1). Decision making regarding medication in hypertensive patients with CAD can be informed from hypertension trials, with ischaemic subgroups, and from studies in ischaemic populations, with hypertensive subgroups. Only one trial [2] has specifically recruited patients with both conditions. Several agents used in these trials merit further consideration.
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Table 1 Relative effects of standard cardiac drugs on hypertension, myocardial ischaemia, and cardiovascular protection |
In animal models, angiotensin-converting enzyme (ACE) inhibitors modulate atherosclerotic pathways by inhibition of angiotensin II formation, bradykinin potentiation, and increased nitric oxide production [3]. Whether this translates into clinical benefits, providing vasculoprotective effects beyond blood pressure reduction, is unclear [4,5•]. Even the renoprotective effects are now under debate [6•]. The Heart Outcomes Prevention Evaluation (HOPE) [7] study demonstrated that ramipril reduced morbidity and mortality in high-risk patients with cardiovascular disease or diabetes plus one additional risk factor. Risk reduction was about three times greater than predicted for the modest reduction in blood pressure (3.3/1.4 mmHg) [8], the difference being attributed to antiatherogenic effects. The HOPE protocol uniquely administered study medication at bedtime, however. Blood pressure measurement approximately 10–18 hours later therefore missed the peak effect after 3–6 hours. A substudy [9] revealed far greater 24-hour ambulatory blood pressure reduction (10/4 mmHg), particularly marked overnight (17/8 mmHg).
The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) [10] studied the effect of perindopril in a low-risk population with predominantly asymptomatic stable CAD. Risk of the composite primary outcome was significantly reduced, largely powered by a reduction in myocardial infarction. No significant difference was observed in cardiovascular or total mortality, however. The results suggested that 50 patients need to be treated for 4 years to prevent one major cardiovascular event.
In contrast to HOPE and EUROPA, addition of an ACE inhibitor to modern conventional therapy provided no further benefit in the recent Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial [4], despite reducing blood pressure by 3.0/1.2 mmHg relative to placebo. There are several reasons for these surprising results (Table 2). The cardiovascular event rate was substantially lower than in previous trials due to exclusion of significant left ventricular systolic dysfunction, prior coronary revascularization, and more intensive medical therapy. Though nearly half of patients had a history of hypertension, mean baseline systolic blood pressure was 133 mmHg, the level achieved using an ACE inhibitor in both HOPE and EUROPA. The higher prevalence of lipid-lowering therapy compared with previous trials, and consequently lower serum cholesterol levels, may also lessen the potential antiatherogenic benefits of ACE inhibition [11]. Finally, significantly fewer patients were receiving maximum-dose ACE inhibitor after 3 years (57.8%) [12•] than in HOPE and EUROPA (70.9 and 74%, respectively). The routine use of ACE inhibitors in patients with hypertension and CAD is therefore no longer advocated, provided blood pressure, cardiovascular risk factors, and symptoms are controlled.
[beta]-Blockers decrease myocardial oxygen demand through reductions in heart rate, blood pressure, and myocardial contractility. The American College of Cardiology/American Heart Association guidelines endorse [beta]-blockers as first-line therapy for chronic stable angina, advocating calcium channel blockers only when [beta]-blockers are contraindicated, poorly tolerated, or unsuccessful (all class I recommendations) [13]. The guidance extrapolates from three bodies of evidence: early, small, short-term studies in stable angina; robust postinfarct reductions in hard endpoints; and purported benefits in hypertension [14]. The former greatly underrepresents the newer long-acting calcium channel blockers, as exemplified by amlodipine. The latter is highly questionable [15,16••]. Even the postinfarct evidence may lack relevance in the modern era. What of the low-risk patient with a minimal troponin rise, preserved systolic function, and stable occasional exertional angina? No antianginal agents, including [beta]-blockers, reduce cardiovascular death or myocardial infarction in patients with stable angina. All decrease frequency of angina and prolong exercise duration before onset of symptoms or ST segment depression [17]. None has proven superiority.
Meta-analysis of 90 randomized controlled trials [18] comparing antianginal agents revealed similar reductions in cardiac events, anginal symptoms, and time to ischaemia. Only a handful of studies, however, used newer drugs such as amlodipine (n = 1), bisoprolol (n = 2), or carvedilol (n = 2), limiting applicability to modern practice. The International Verapamil-Trandolapril Study (INVEST) [2], the only trial to recruit patients with both hypertension and CAD, confirmed the equivalence of verapamil–trandolapril and atenolol–hydrochlorothiazide based strategies in preventing death, myocardial infarction, or stroke (adjusted hazards ratio 0.98 [0.91–1.07], P = 0.69). Though the study sought to compare multidrug regimens, open blinding and use of ACE inhibitors and diuretics in both arms served to attenuate differences between the two strategies. In the respective groups, 81.5% of patients received verapamil vs. 77.5% atenolol, 82.0 vs. 71.6% received an ACE inhibitor, and 63.0 vs. 81.4% a diuretic at 24 months. Conclusions regarding the contribution of any single agent are not possible. Both groups achieved similar blood pressure reduction (18.7/10.0 vs. 19.0/10.2 mmHg) and number of patients reaching Joint National Committee on Hypertension VI blood pressure targets (71.7 vs. 70.7%, P = 0.18). This corresponded with marked decreases in the prevalence of angina in both verapamil-based and atenolol-based groups, from 66.2 and 67.0% to 27.3 and 28.3%, respectively. The message is clear. Blood pressure reduction is the key, with no evidence of [beta]-blocker superiority.
In the Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA) [19•], the amlodipine–perindopril strategy reduced cardiovascular mortality and major cardiovascular events, particularly stroke, compared with the atenolol–bendroflumethiazide regimen. Subsequent meta-analysis [16••] suggested that [beta]-blockers reduce risk of stroke in primary hypertension by about half that expected (only 19%), the risk being 16% higher than for other drugs. Patients with coexistent CAD are unlikely to differ. Indeed, a similar nonsignificant trend was observed in INVEST. Despite this, [beta]-blockers have one undeniable advantage as first-line agents over rate-limiting calcium antagonists in these patients. They may be combined with newer non-rate-limiting calcium antagonists, notably amlodipine, to provide dual antianginal and antihypertensive therapy.
In a meta-analysis [20] of 31 randomized trials involving nearly 25 000 patients, long-term [beta]-blockade following myocardial infarction significantly reduced mortality and reinfarction by about 25%, with no such benefits observed in short-term trials. The recent Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) [21••] in more than 45 000 patients, 43% with known hypertension, reinforces this evidence and guides the timing of initiation. Immediate intravenous then oral metoprolol until discharge failed to reduce overall risk of death, reinfarction, or cardiac arrest following acute myocardial infarction. Early increased risk of cardiogenic shock (days 0–1) counterbalanced reduced risk of reinfarction and ventricular fibrillation (significant from day 2 onwards). Consequently the effect of metoprolol on the combined efficacy and safety outcome of death, reinfarction, arrest, or shock was adverse initially and beneficial thereafter (P = 0.0003 for trend in odds ratio). Systolic blood pressure lower than 120 mmHg, and to a lesser extent 160 mmHg or higher, increased the risk of cardiogenic shock with metoprolol. Conservative blood pressure reduction that avoids coronary hypoperfusion is critical in the acute situation. [beta]-Blockers should be commenced only once a patient's haemodynamic condition has stabilized, even in those with hypertension or tachycardia.
Two recent studies support the use of dihydropyridine (non-rate-limiting) calcium channel blockers in CAD. ACTION (A Coronary Disease Trial Investigating Outcome with Nifedipine GITS [gastrointestinal therapeutic system]) [22] studied the effects of nifedipine in 7665 patients with treated stable angina pectoris, finding no reduction in the primary composite endpoint. In the prespecified hypertensive subgroup (52%) with blood pressure above 140/90 mmHg, however, nifedipine improved major cardiovascular event-free survival by 13% (P < 0.05), principally due to reductions in coronary angiography, stroke, and new overt heart failure [23•]. The concurrent blood pressure reduction (6.6/3.5 mmHg) highlights the importance of improving control in patients with established CAD.
The Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study [24] compared the effects of amlodipine, enalapril, and placebo in 1991 patients with angiographic CAD. Although 60.5% of patients had documented hypertension, mean baseline blood pressure was normal (129/78 mmHg) due to exclusion of patients with diastolic pressure above 100 mmHg. Amlodipine significantly reduced the primary composite endpoint of major cardiovascular events relative to placebo (0.69 [0.54–0.88], P = 0.003), largely due to fewer hospitalizations for angina and coronary revascularization procedures. Despite almost identical blood pressure reductions, enalapril failed to significantly reduce the primary or secondary outcomes. An intravascular ultrasound substudy demonstrated a trend toward less progression of atherosclerosis in the amlodipine group, which was significant in those with systolic blood pressures above the mean (P = 0.02). The CAMELOT study provides two important insights. Firstly, ACE inhibition offered no specific vasculoprotective effects beyond an active comparator. Secondly, though the two cannot be directly linked, fewer cardiovascular events occurred alongside lowering of blood pressure already considered within normal limits. In the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial [25], nearly half of patients had verified coronary disease. Compared with valsartan, amlodipine reduced blood pressure more effectively and significantly reduced risk of myocardial infarction and frequency of angina. Together these studies form a compelling argument for including amlodipine in treating patients with both hypertension and CAD.
Statin therapy is undoubtedly the single most important risk factor intervention beyond blood pressure reduction. In the ASCOT Lipid Lowering Arm [26], reductions in coronary events were apparent at 30 days and significant within 3 months. The National Cholesterol Education Program guidelines [27] introduced a low-density lipoprotein cholesterol (LDL-c) target of 1.8 mmol/l (70 mg/dl) for very high-risk patients, alongside a target of 2.5 mmol/l (100 mg/dl) for high-risk patients. Two recent trials suggest that intensive compared with moderate lipid lowering, and the lower LDL-c target, may be appropriate for all patients with CAD. The Treating to New Targets (TNT) [28••] study randomly assigned 10 000 patients with stable CAD to receive 80 mg or 10 mg of atorvastatin daily, lowering mean LDL-c to 2.0 mmol/l and 2.6 mmol/l, respectively. Major cardiovascular events, the primary outcome, were significantly reduced by 22% (0.78 [0.69–0.89], P < 0.001). Similar benefits occurred in the broader composite outcomes of any cardiovascular or any coronary event. Results were tempered by a nonsignificant increase in noncardiovascular deaths, however, leading to a call for further reassurance as to the safety of atorvastatin 80 mg/day [29].
Concerns regarding safety were lessened by the recent Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study [30•]. Nearly 9000 patients with a previous myocardial infarction were randomly assigned to receive high-dose atorvastatin 80 mg/day or usual-dose simvastatin 20 mg/day, reducing mean LDL-c to 2.1 mmol/l and 2.7 mmol/l, respectively. The aggressive lipid lowering failed to achieve a significant reduction in the primary outcome, defined as coronary death, myocardial infarction, or resuscitated cardiac arrest (0.89 [0.78–1.01], P = 0.07). Risk of major cardiovascular events including stroke, the primary outcome in the TNT study, however, was significantly reduced by 13% (0.87 [0.77–0.98], P = 0.02). More importantly, no excess of noncardiovascular deaths was observed in the atorvastatin group. Although no difference was observed in cardiovascular or total mortality in either the IDEAL or TNT studies, neither was powered for this endpoint. In both, serious myopathy and rhabdomyolysis were rare and of similar frequency in each treatment group. Patients receiving high-dose atorvastatin had more nonserious adverse events resulting in drug discontinuation, including persistent transaminase elevation (about 1.0%).
The importance of LDL-c lowering was highlighted by the Cholesterol Treatment Trialists' (CTT) Collaborators' meta-analysis [31••] of 14 trials involving 90 000 patients. Statin therapy reduced coronary mortality, revascularization, myocardial infarction, and stroke by about 20% per 1 mmol/l decrement in LDL-c, with a corresponding 12% proportional reduction in all-cause mortality. Benefits were consistent in all subgroups including patients with hypertension, pretreatment LDL-c less than 2.6 mmol/l, and even LDL-c less than 2.0 mmol/l. Absolute benefit was determined by the absolute risk of events and the absolute reduction in LDL-c achieved. Thus the overall risk reduction of about 20% per mmol/l LDL-c reduction translated into 48 fewer patients having major cardiovascular events per 1000 among those with preexisting CAD, compared with 25 per 1000 among patients with no such history. Rather than achieving specific target levels, the goal should be substantial absolute reductions in LDL-c, irrespective of baseline cholesterol.
Cardiovascular mortality increases continuously across the full blood pressure range from 115/75 mmHg, doubling with each increment of 20/10 mmHg [32,33]. Thresholds guide when to initiate treatment in low-risk patients. Such arbitrary limits are less relevant once CAD is established. Lowering blood pressure in these patients reduces cardiovascular events irrespective of baseline values, as demonstrated in the CAMELOT study. As with diabetes, a target blood pressure of 130/80 mmHg is therefore now recommended [34••].
A small number of modifiable risk factors account for the majority of cardiovascular risk. In the INTERHEART study [35], just five risk factors accounted for 80% of the population-attributable risk: lipids (odds ratio 3.25), smoking (2.87), diabetes (2.37), hypertension (1.91), and obesity (1.12). Daily consumption of fruits and vegetables (0.70), regular physical activity (0.86), and moderate alcohol consumption (0.91) were protective factors. Physicians frequently underestimate the benefits of smoking cessation, exercise, and diet. Advice, counselling, and nicotine replacement products are effective in 25% of smokers [36•]. Exercise training improves anginal symptoms, increases exercise capacity, and reduces myocardial ischaemia [37]. Meta-analysis of cardiac rehabilitation studies [38] suggests that exercise training reduces cardiovascular mortality while simultaneously improving blood pressure and lipid profile. In a recent randomized trial on highly selected patients [39], regular physical exercise improved event-free survival compared with percutaneous intervention.
The prognosis for patients with hypertension and ischaemic heart disease is critically dependent on addressing the three areas of blood pressure lowering, lessening ischaemia, and providing cardiovascular protection. Many of the commonly used agents have complementary effects in these areas (Table 1). All modifiable risk factors must be aggressively managed. Some cardiologists place more emphasis on the immediate benefits of percutaneous revascularization. This approach offers no benefit over conservative medical treatment in terms of death, myocardial infarction, or subsequent revascularization [40••]. The cornerstone of treatment is blood pressure reduction. Multiple-drug therapy is required using agents with both antihypertensive and antianginal properties. Combining a [beta]-blocker with amlodipine is preferable. For [beta]-blocker-intolerant patients, rate-limiting calcium antagonists are equally effective. ACE inhibitors are appropriate if blood pressure control remains suboptimal. Antiplatelet and statin therapy are mandatory in all patients. Compliance is a major issue [41•] and requires support to facilitate understanding of the importance of lifestyle modifications and drug therapy in reducing risk of future cardiovascular events. Recent years have seen a marked reduction in cardiovascular event rates, largely due to these measures. Despite this, basic cardiovascular risk factors remain underdiagnosed and poorly treated in many regions of the world [42••]. This is unacceptable in the 21st century when there is such unequivocal benefit in a strategy combining blood pressure control with vasculoprotective therapies.
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