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Studio Italiano Sugli Effetti CARDIOvascolari del Controllo della Pressione Arteriosa SIStolica - Cardio-Sis
Description:
Current Joint National Committee-7 guidelines recommend that blood pressure (BP) be reduced to a goal of 140/90 mm Hg or lower in nondiabetic patients with hypertension. The Cardio-Sis trial sought to evaluate whether tighter control (systolic goal <130 mm Hg) would be associated with a clinical benefit in these patients.
Hypothesis:
Tighter control of systolic BP (SBP) with a goal of <130 mm Hg would be associated with a significant reduction in the incidence of left ventricular hypertrophy (LVH), as well as clinical outcomes, in nondiabetic patients with hypertension, as compared with usual control, with a goal of <140 mm Hg.
Study Design
Study Design:
Patients Screened: 1,193
Patients Enrolled: 1,111
Mean Follow Up: 2 years
Mean Patient Age: 67 years
Female: 59
Patient Populations:
- Age ≥55 years
- SBP >150 mm Hg
- Antihypertensive treatment for at least 12 weeks prior to enrollment
- At least one of the following risk factors: smoking, family history of premature CAD, established CAD/PAD, previous TIA/stroke, total cholesterol >201 mg/dl, high-density lipoprotein cholesterol <39 mg/dl, low-density lipoprotein cholesterol >135 mg/dl
Exclusions:
- Fasting glucose >126 mg/dl
- Conditions associated with reduced life expectancy
- Renal dysfunction (creatinine >2 mg/dl)
- Clinically relevant hematologic or hepatic disorders
- Valvular heart disease
- Disorders associated with a confusion in the ECG diagnosis of LVH (complete right/left bundle branch block, Wolff-Parkinson-White syndrome, previous Q-wave MI, paced rhythm)
- AF
- Substance abuse
Primary Endpoints:
- ECG evidence of LVH at 2 years
Secondary Endpoints:
- Composite of death, MI, stroke, TIA, CHF, angina with evidence of ischemia, new-onset AF, coronary revascularization, aortic dissection, occlusive PAD, and renal failure needing dialysis
- Single components of the composite endpoint listed above
- Baseline-adjusted difference between the two groups in the achieved SBP
Drug/Procedures Used:
After a run-in period of 1-2 weeks, where a SBP of 150 mm Hg or higher was confirmed at two different times, patients were randomized to tight (<130 mm Hg) or usual (<140 mm Hg) SBP control. Treatment to lower BP was open-label and tailored to every patient’s needs.
Antihypertensive drug treatment included various combinations of previous drugs (background therapy) plus drugs made available for the purpose of the study, including furosemide 25 mg/day, ramipril 5 or 10 mg/day, telmisartan 80 mg/day, amlodipine (5 or 10 mg/day), bisoprolol (5 mg/day), or transdermal clonidine (2.5 or 5 mg/day). At every visit, the choice of drugs in individual patients was left to the discretion of the investigators. In the tight-control group, one SBP reading higher than 130 mm Hg at any visit led to intensification of treatment. Conversely, in the usual-control group, achievement of an SBP <130 mm Hg entailed down-titration of treatment.
Concomitant Medications:
Diuretics (44%), beta-blockers (35%), angiotensin-converting enzyme inhibitors (44%), angiotensin-receptor blockers (32%), calcium channel blockers (34%), alpha-1 blockers (9%), statins (23%), and aspirin (19%)
Principal Findings:
A total of 1,111 patients were enrolled, 553 to usual control, and 558 to tight control. Baseline characteristics were fairly similar between the two groups. The mean baseline BP was 163.3/89.7 mm Hg, with a heart rate of 71 bpm. About 12% had coexisting coronary artery disease (CAD), 76% had dyslipidemia, and 22% were current smokers. Baseline creatinine was 0.95 mg/dl.
About 66.9% of the patients in the usual-control group, and 78.7% in the tight-control group achieved goal BP at 2 years, with a mean BP of 135.6/78.7 mm Hg and 131.9/77.4 mm Hg, respectively. BP decreased by 25.8/9.9 mm Hg at 1 year and by 27.7/10.8 mm Hg at 2 years in the usual-control group, and by 30.5/11.4 mm Hg at 1 year and 31.3/12.3 mm Hg at 2 years in the tight-control group (p < 0.0001). The BP difference between the two groups averaged 3.8/1.5 mm Hg.
The incidence of LVH on ECG was significantly lower in the tight-control group compared with usual-control groups (11.4% vs. 17.0%, odds ratio [OR] 0.63, 95% confidence interval [CI] 0.43-0.91, p = 0.013). The composite endpoint of death, myocardial infarction (MI), stroke, transient ischemic attack (TIA), congestive heart failure (CHF), angina with evidence of ischemia, new-onset atrial fibrillation (AF), coronary revascularization, aortic dissection, occlusive peripheral arterial disease (PAD), and renal failure needing dialysis was also significantly lower in the tight-control arm (4.8% vs. 9.4%, OR 0.50, 95% CI 0.31-0.79, p = 0.003). Of these individual endpoints listed in the composite endpoint above, new-onset AF (1.8% vs. 3.8%, p = 0.044) and coronary revascularization (0.9% vs. 2.7%, p = 0.032) were significantly lower in the tight-control arm; the incidence of other endpoints, including mortality (0.7% vs. 0.9%, p = 0.70), was similar.
The authors noted that patients in the tight-control arm had a higher usage of diuretics and angiotensin-receptor blockers. The incidence of adverse events (12.9% vs. 11.0%), including hypotensive episodes (0.9% vs. 0.4%), was similar between the two groups.
Interpretation:
The results of this trial indicate that a more aggressive SBP goal of <130 mm Hg is associated with a reduction in LVH, as well as a clinical benefit, in nondiabetic patients with hypertension (but with at least one other CAD risk factor), as compared with the current goal of <140 mm Hg. The choice of a surrogate endpoint (LVH by ECG criteria) by the investigators as a primary endpoint does limit the clinical significance of these findings somewhat, although LVH is a well-established marker of cardiovascular mortality and morbidity.
Moreover, the absolute difference in SBP between the two arms was only about 3.8 mm Hg at 2 years. It is also unknown if these differences will be maintained over a longer duration of follow-up, since most hypertensive patients are required to stay on these medications life-long. Further, the population studied was 100% Caucasian; thus, it is unknown if these differences hold true for other ethnic groups as well.
However, given that there was no difference between the two groups in the incidence of side effects or hypotensive episodes, a more aggressive strategy to reduce SBP to <130 mm Hg in nondiabetic patients with hypertension, and at least one cardiovascular risk factor, seems like a reasonable strategy. If these findings are confirmed by ongoing clinical trials, current recommendations regarding treatment goals for nondiabetic hypertensive patients will likely need to be revised.
References:
Verdecchia P, Staessen JA, Angeli F, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. Lancet 2009;374:525-33.
Keywords: Hypertrophy, Left Ventricular, Coronary Artery Disease, Ischemic Attack, Transient, Risk Factors, Peripheral Arterial Disease, Blood Pressure, Electrocardiography, Creatinine, Furosemide, Benzoates, Cholesterol, Dyslipidemias, Benzimidazoles, Hypertension, Angiotensin Receptor Antagonists, Ethnic Groups, Myocardial Infarction, Stroke, Diuretics, Clonidine, Ramipril, Heart Rate, Smoking, Renal Insufficiency, Heart Failure, Amlodipine, Bisoprolol
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