Tight Blood Pressure Control and Cardiovascular Outcomes Among Hypertensive Patients With Diabetes and Coronary Artery Disease

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Cooper-DeHoff RM. "Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease". JAMA. 2010. 304(1):61-68.
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Clinical Question

In patients with type 2 diabetes mellitus and coronary artery disease, does tight systolic blood pressure control (<130 mmHg) compared to usual systolic control (<140 mmHg) improve cardiovascular outcomes?

Bottom Line

Tight systolic blood pressure control (<130 mmHg) in patients with hypertension, type 2 diabetes mellitus and coronary artery disease (CAD), was not associated with improved cardiovascular outcomes compared with usual systolic blood pressure control (<140 mmHg).

Major Points

Previous recommendations for blood pressure targets in patients with type 2 diabetes and hypertension were aimed to achieve tight control of systolic pressure to a goal of <130 mmHg to prevent associated micro and macrovascular morbidity and mortality. This subgroup analysis of patients with hypertension, type 2 diabetes mellitus, and CAD from the INVEST trial, showed there is no further reduction in morbidity between patients treated to a goal of <130 mmHg and those treated to a goal of <140 mmHg. It was discovered that patients with hypertension treated to a goal of <130 mmHg had an increased risk of all-cause mortality persisting over the long term, compared to patients treated to a blood pressure goal of <140 mmHg. Currently, there is no evidence to support treating patients with hypertension, type 2 diabetes mellitus and CAD to a systolic blood pressure <130 mmHg. These patients should be treated to a goal systolic blood pressure of 130-139 mmHg, as well as, maintain a healthy lifestyle to further reduce their risk for long term complications of diabetes.

Guidelines

The American Diabetes Association recommends a treatment target for systolic blood pressure of <140 mmHg for patients with type 2 diabetes mellitus and hypertension.[1]

Design

  • Observational, secondary subgroup analysis of 6,400 of 22,576 participants with hypertension, type 2 diabetes mellitus and CAD in the INVEST trial.
  • Setting: 862 sites in 14 countries.
  • Enrollment: September 1997 through December 2000.
  • Follow-up was conducted through March 2003. An extended follow-up was conducted for US participants through August 2008 via the National Death Index.

Population

Inclusion Criteria

  • Age 50 years or older
  • Essential hypertension (defined by the JNC VI) requiring drug therapy
  • Documented CAD (remote confirmed MI, abnormal coronary angiogram (>50% narrowing of at least one major coronary artery), abnormalities on two different types of stress tests or diagnosis of classical angina pectoris)
  • This study analyzed a subgroup of the participants, who met the inclusion criteria listed above, and had type 2 diabetes mellitus.

Exclusion Criteria

  • Unstable angina, angioplasty, coronary bypass or stroke within the previous month
  • Beta-blocker use within the previous 2 weeks or previous year for post-MI patients
  • Sinus bradycardia, sick sinus syndrome or atrioventricular block of more than first degree in the absence of an implanted pacemaker
  • Severe (New York Heart Association class IV) heart failure
  • Severe renal (creatinine ≥4.0 mg/dL) or hepatic failure
  • Contraindication to verapamil

Baseline Characteristics

All characteristics are considered not significantly different unless noted in the text.

  • Age (years): 65 vs 66
  • Age (>70): 641 vs 629
  • BMI (kg/m2): 30 vs 31
  • Systolic BP (mmHg): 144 vs 149
  • Women: 49% vs 54%
  • Race/ Ethnicity

        White: 40% vs 46%
        Black: 9.3% vs 15%
        Hispanic: 48% vs 37%
        Other/multiracial: 2.8% vs 2%

  • Prior stroke/TIA: 8.2% vs 8.5%
  • LVH: 26% vs 22%
  • Heart Failure (NYHA class I-III): 8.8% vs 6.8%
  • Smoking history: 48% vs 45%
  • Renal impairment: 3.5% vs 2.4%
  • Lipid lowering medication: 44% vs 43%
  • Aspirin or other antiplatelet: 61% vs 58%

Interventions

Patients were randomly assigned to receive a calcium channel antagonist (verapamil) or a beta-blocker (atenolol) as first-line treatment. Second and third line treatments included an angiotensin-converting enzyme inhibitor, a diuretic, or both as needed to achieve a blood pressure of <130/85 mmHg. All patients in this study subgroup received an angiotensin-converting enzyme inhibitor (ACE inhibitor, tandolapril) in addition to their study drug secondary to their diagnosis of type 2 diabetes mellitus at baseline. Patients were then categorized into one of three group, as follows, based on their level of blood pressure control/maintenance.

  1. Tight control: systolic BP <130 mmHg
  2. Usual control: systolic BP <140-130 mmHg
  3. Uncontrolled: systolic BP ≳140 mmHg

Outcomes

Primary Outcomes

First occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke

  • Tight control 12.7% CI (11.3-14.1) vs uncontrolled 19.8% CI (18.1-21.5)
  • Tight control (12.7%) vs usual control (12.6%): [adjusted HR, 1.11; 95% CI, 0.93-1.32; P = .24]
  • Usual control (12.6%) vs uncontrolled (19.8%): [adjusted HR, 1.46; 95% CI, 1.25-1.71; P < .001, NNT= 14]

Secondary Outcomes

All-cause mortality
Tight control (22.8%) vs usual control (21.8%): [adjusted HR, 1.15; 95% CI, 1.01-1.32;P = .04, NNH=100]
Nonfatal MI
Tight control: 1.3% CI (0.8-1.8)
Normal control: 1.7% CI (1.1-2.2)
Uncontrolled: 3.1% CI (2.4-3.8)
Total MI
Tight control: 4.8% CI (3.9-5.7)
Normal control: 5.1% CI (4.1-6)
Uncontrolled: 8.5% CI (7.3-9.7)
Nonfatal stroke
Tight control: 1.0% CI (0.6-1.4)
Normal control: 1.3% CI (0.8-1.8)
Uncontrolled: 2.4% CI (1.7-3.0)
Total stroke
Tight control: 1.5% CI (1.0-2.0)
Normal control: 1.7% CI (1.1-2.2)
Uncontrolled: 3.2% CI (2.5-4.0)

Subgroup Analysis

Adverse Events

Criticisms

The assignment of study arms was based on an ability to achieve a BP target as opposed to designing treatment to reach a BP target, yet the authors’ conclusions seem to conclude that patients should be treated to a certain value. Rather, this research would be better interpreted as a predictor of morbidity and mortality based on a patient’s response to therapy.

It should be noted that atenolol was the BB used in this trial. Atenolol has been shown to be inferior to other BBs, such as metoprolol and carvedilol, in patients with HTN and CAD for secondary prevention. Verapamil, a non dihydropyridine calcium channel blocker, was also used in this study instead of a more appropriate first line dihydropyridine calcium channel blocker for this population. The individual breakdown of which antihypertensives each patient received were not provided for the three groups. However, it was noted that 50% of patients in the tight-control group were taking ≥3 antihypertensive drugs. In the usual control and uncontrolled groups, >67% of patients were taking ≥3 antihypertensive agents. Of all the patients in the 3 groups, ≥ 75% of patients were taking a renin angiotensin aldosterone system (RAAS) antagonist.

Funding

The INVEST trial was funded by a grant from Abbott Laboratories. It was noted that Abbott Laboratories had no role in the design or conduct of the study, collection or analysis of the data, or preparation or approval of the manuscript.

Further Reading