The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends a blood pressure (BP) goal of <140/90 mm Hg in most patients with hypertension and a goal of <130/80 mm Hg in patients with diabetes or chronic kidney disease. A recent scientific statement from the American Heart Association suggested adding patients with known coronary artery disease, carotid disease, peripheral artery disease, an abdominal aortic aneurysm, left ventricular dysfunction, or a calculated 10‐year Framingham risk score of at least 10% to the group of patients with a BP goal of <130/80 mm Hg. These recommendations were made despite a lack of level I clinical trial evidence for benefit of more intensive treatment of BP in those patient populations.
These recommendations are largely aimed at reducing the incidence of hard cardiovascular events such as myocardial infarction (MI), stroke, or heart failure. In patients with hypertension, left ventricular hypertrophy (LVH) is a major independent risk factor for stroke, MI, sudden cardiac death, and cardiovascular mortality. Yet, neither JNC 7 nor the American Heart Association (AHA) Scientific Statement specify a more aggressive BP goal in patients with LVH, and prevention of LVH is not emphasized in current guidelines. Whether more aggressive BP lowering would effectively reduce the incidence of LVH was recently tested in the Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica (Cardio‐Sis) trial. In this open‐label, industry‐supported trial conducted between February 2005 and February 2007, Italian researchers enrolled 1111 Italian hypertensive nondiabetic patients (93% of those screened). Inclusion criteria included age 55 years or older, a baseline systolic BP of ≥150 mm Hg, use of antihypertensive therapy for at least 12 weeks, and at least 1 additional risk factor (cigarette smoking, dyslipidemia, family history of premature cardiovascular disease, previous transient ischemic attack or stroke, or established coronary or peripheral artery disease). Patients were excluded if they had a history of diabetes, renal dysfunction, valvular heart disease, liver disease, atrial fibrillation, substance abuse, or a limited life expectancy. Eligible participants entered a run‐in phase to make sure that at two visits 7 to 14 days apart their systolic BP on their present antihypertensive regimen was ≥150 mm Hg. They were then randomized in a 1:1 ratio to receive antihypertensive drug treatment to achieve either usual systolic BP control (<140 mm Hg) (n=553) or tight systolic BP control (130 mm Hg) (n=558). They were followed up every 4 months for 2 years. At baseline and at 1 and 2 years, patients had a 12‐lead electrocardiogram (ECG) and laboratory blood tests performed. Treatment was open‐label, with all classes of antihypertensive drugs available. Intensification or down‐titration of treatment was permitted in order to achieve the specified BP goals. Drug classes were evenly distributed at baseline, except in the usual‐control group where more patients were taking a diuretic and fewer were taking an angiotensin receptor blocker (ARB). The primary study outcome was the prevalence of ECG‐LVH at the final 2‐year visit. The main prespecified secondary outcome was a composite of all‐cause mortality, fatal or nonfatal MI, fatal or nonfatal stroke, transient ischemic attack, New York Heart Association stages III or IV heart failure requiring admission to the hospital, angina pectoris with objective evidence of myocardial ischemia, new‐onset atrial fibrillation, coronary revascularization, aortic dissection, occlusive peripheral arterial disease, and renal failure requiring dialysis. Other predefined secondary outcomes included the single components of the main composite secondary outcome. Only one patient was lost to follow‐up.
BP decreased by 27.7/10.8 mm Hg at 2 years in the usual‐control group and by 31.3/12.3 mm Hg at 2 years in the tight‐control group (P<.0001) (difference between the two groups averaging 3.8 mm Hg systolic [95% confidence interval (CI), 2.4–5.2 mm Hg; P<.001] and 1.5 mm Hg diastolic [95% CI, 0.6–2.4 mm Hg; P=.041]). The final BP was 135.6/78.7 mm Hg in the usual‐control group and 131.9/77.4 mm Hg in the tight‐control group, with 27.3% of the usual‐control group <130 mm Hg at the end of 2 years vs 72.2% of the tight‐control group.
The incidence of the primary outcome, ECG‐LVH was significantly lower in the tight rather than usual‐control group (11.4% vs 17.0%; odds ratio, 0.63; 95 CI, 0.43–0.91; P=.013). The composite secondary outcome was also significantly less likely to occur in the tight‐control group compared with the usual‐control group (4.8% vs 9.4%; hazard ratio, 0.50; 95% CI, 0.31–0.79; P=.003). Of the specific components of the secondary outcome, new‐onset atrial fibrillation and coronary revascularization occurred less in the tight control group. There was no difference between groups in any of the other secondary outcomes. Adverse reactions were rare and mild and occurred at a similar rate in the two treatment arms. The number of antihypertensive drug classes used increased in both study groups (P<.0001), increasing from 2.0 at randomization to 2.9 at 2 years. Only diuretics were more likely to be used in the tight‐control group compared with the usual‐care group when adjustment for imbalances at baseline were made (P=.009). In addition, a statin and aspirin were more likely to be used at the end of the trial, although there was no difference noted between the groups.
The authors conclude that in nondiabetic hypertensive individuals older than 55 with at least one other risk factor, tight control of systolic BP, to a goal <130 mm Hg, decreases the likelihood of developing ECG‐LVH and specific clinical events compared with a usual systolic BP goal <140 mm Hg. These data suggest that future recommendations should consider more aggressive BP goals in this patient population.—Verdecchia P, Staessen JA, Angeli F, et al; on behalf of the Cardio‐Sis investigators. Usual vs tight control of systolic blood pressure in non‐diabetic patients with hypertension (Cardio‐Sis): an open‐label randomized trial. Lancet. 2009;374:525‐533.
Comment
Despite decades of BP research, determining appropriate BP goals in specific patient populations remains controversial. Certainly observational data suggests that “lower is better,” with a log‐linear relationship between observed BP and the risk of cardiovascular events. However, the benefit of aggressively treating hypertension must be weighed against the potential safety and tolerability issues associated with increased prescription of antihypertensive medications. More aggressive BP control is also likely to be associated with a diminishing absolute benefit, and, in our current environment, must also be demonstrated to be cost‐effective as well as clinically effective. With the exception of some limited data in patients with diabetes or chronic kidney disease, there is a paucity of randomized clinical trials that have primarily compared different BP goals in patients with primary hypertension. Previously, the most complete attempt to study this question was the Hypertension Optimal Treatment (HOT) study, which was published more than a decade ago and focused on diastolic, rather than systolic, BP. Given the paucity of good‐quality randomized trials, the BP target of <140/90 mm Hg established by JNC 7 and other organizations must be considered relatively arbitrary.
The results of the present study, Cardio‐Sis, suggest that in older hypertensive patients without diabetes, a systolic BP treatment goal <130 mm Hg is associated with decreased risk of developing LVH compared with a goal <140 mm Hg. The incidence of the secondary composite cardiovascular outcome was also significantly reduced with the more aggressive target of <130/80 mm Hg. However, the total number of events was few, and only new‐onset atrial fibrillation and the need for coronary revascularization, not the “hard” clinical end points such as stroke and MI, were individual components of the secondary outcome that drove this finding. Cardio‐Sis also has a number of important limitations that must be considered. The study was small and all of the patients were white and from Italy. Whether the outcomes apply to other ethnicities, such as African Americans, remains unclear. Additionally, the study was not double‐blinded and recognition of some of the secondary end points, particularly incident heart failure and coronary revascularization, could have been affected by the lack of blinding. Overall, the number of secondary end points was very small, and follow‐up was limited to 2 years. Perhaps most importantly, the primary, prespecified end point was incident LVH. While LVH has certainly been associated with increased risk of clinical cardiovascular events in observational studies, it still should be considered a “‘surrogate” rather than a “hard” clinical end point. It should be noted that the incidence of LVH was determined based on ECG, rather than more accurate echocardiographic, criteria. Given these limitations, the results of Cardio‐Sis should be considered hypothesis generating, rather than guideline changing.
A recent Cochrane analysis including 7 hypertension treatment trials involving more than 22,000 high‐risk participants found that there was little evidence to support achieving a BP goal of <140/90 mm Hg in patients without diabetes or chronic kidney disease. It is shocking that despite the amount of time and effort that has gone into studying the treatment of hypertension, we still do not have adequately designed and powered studies to answer this fundamental clinical question. In the absence of such studies, based on observational data, it may be reasonable to expand the population of patients with a more aggressive BP goal of <130/80 mm Hg to those with established heart or vascular disease, in accordance with the recent scientific statement from AHA. However, before we recommend a more aggressive BP goal in most patients with hypertension we need better data. Currently, the National Heart, Lung, and Blood Institute (NHLBI) is designing and implementing plans for the Systolic Blood Pressure Intervention Trial (SPRINT), which will randomize 7500 nondiabetic hypertensive patients 55 years and older (one third of whom will have chronic kidney disease) to a BP goal of either <120 mm Hg or a goal of <140 mm Hg. It is absolutely imperative that this landmark clinical study be given the highest priority. Rather than changing our present recommendations, the results of Cardio‐Sis should be considered a call to action to fill this important void in hypertension research.