Prognostic value of blood pressure control delay in newly diagnosed hypertensive patients

The original article, ‘The Prognostic Value of Blood Pressure Control Delay in newly Diagnosed Hypertensive Patients,’ by Martín-Fernández et al.[1] represents a key extension of previous reports on prompt blood pressure (BP) control and clinical outcomes. The current report included 18 721 newly diagnosed hypertensive patients from 45 primary healthcare centers in Barcelona, Spain, followed a mean of 5.4 years (101 093 patient-years). All-cause mortality was ∼15% greater among patients in the upper tertile of time to BP control, that is, at least 125 days, than in those more promptly controlled. Six other clinical factors were independently associated with all-cause mortality (age, type 2 diabetes, and smoking were directly related; female sex, hypercholesterolemia, and DBP were inversely related). Results were similar when data were analyzed by time-to-control less than 1 month, 1–3 months, and greater than 3 months. Those controlled after 3 months had ∼15% higher all-cause mortality than patients controlled at less than 1 month. SBP was not significantly related to all-cause mortality. Yet, Stage 2 (BP 160–179/100–109) and Stage 3 hypertension (BP ≥180/≥110) were independently linked to BP control at least 125 days or more after starting treatment. Other variables related to control at least 125 days or more were BMI, diabetes mellitus (positive), and female sex (negative). As BP values were not captured during follow-up, separating the effects of time-to-control and variation of time-in control during the follow-up period were not possible. The current study is unique, yet prior reports provide insight on important and related questions that were not addressed. The Valsartan Amlodipine Long-term Use Evaluation (VALUE) study [2,3] showed that individuals with better BP responses or control at 1, 3, and 6 months were associated with significantly fewer fatal and nonfatal cardiac events (primary outcome) than respective comparison groups. The primary outcome occurred more often in the first 3 months of VALUE in patients randomized to valsartan than amlodipine (odds ratio 1.78, 95% confidence interval 1.22–2.60) [2]. The differential outcome was attributed mainly to a 3.8/2.2 mmHg lower BP of patients randomized to amlodipine than valsartan in the first 3 months. The variance in BP between treatment groups fell over time and the primary outcome was not different after 6 months or end of study. The conclusion that between-group BP differences accounted for more cardiac events with valsartan in the early phases of VALUE raised concern. The counter-argument posits that an initial rise of BP in previously treated patients accounted for early cardiac events. This concern was partially addressed by an analysis comparing outcomes in previously treated patients without an increase of BP and newly treated patients with a fall in SBP fall at least 10 mmHg in the first month (immediate) to non-immediate (>1 month) responders [3]. Immediate responders (valsartan or amlodipine combined) had fewer primary (cardiac) events than nonimmediate responders. Patients attaining BP control in the first 6 months also had fewer primary events than slower responders. The report provides evidence for a prompt, BP-dependent decline in cardiac events in treated patients. A retrospective analysis of United Kingdom Prospective Diabetes Study (UKPDS) [4] data estimated the impact of 1-year and 10-year differences in BP of 130 mmHg (‘controlled’) versus 150 mmHg (‘uncontrolled’). A 1-year delay was associated with 14 and a 10-year delay with 428 more cardiovascular and renal events/10 000 patient years. The impact of immediate versus delayed antihypertensive therapy was assessed in the Systolic Hypertension in Europe Trial (Syst-Eur) [5]. Syst-Eur began as a randomized, double-blind trial of nitrendipine with add-on enalapril and hydrochlorothiazide as needed to lower SBP to less than 150 mmHg versus placebo. The trial was stopped after a median follow-up of 2 years because of a 42% reduction in the primary outcome of fatal and nonfatal stroke with active treatment. Syst-Eur continued four more years with open-label active treatment in all patients. During open-label follow-up, no differences were observed in stroke or cardiovascular events between patients originally randomized to active treatment versus placebo. Yet, at a median follow-up of 6.1 years, those initially randomized-to-active therapy had 28% fewer strokes (P = 0.01) and 15% fewer cardiovascular events (P = 0.03) than those randomized to placebo. A 2-year delay in active therapy led to an excess of seven strokes and 25 major cardiovascular events at 6 years. The impact of TIme per year spent by newly identified hypertensive patients at BP care TaRgEt (TITRE) [6] was assessed on the primary endpoint of cardiovascular disease (CVD) composite of incident CVD death, acute myocardial infarction, and stroke; incident heart failure; and composite of any incident CVD and death. Among 2.68 million patients in England seen from January 1997 to March 2010, 150 130 newly diagnosed hypertensive patients met inclusion criteria. With median follow-up of 5 years, 5684 patients (3.4%) had incident fatal and nonfatal CVD. With reference time-in-control/year at 3.0–5.9 months, the CVD composite occurred more often in those controlled less than 3 months [odds ratio (OR) 1.74, 95% confidence interval (CI) 1.19–2.70] and less often in those controlled 6.0–8.9 (OR 0.73, 95% CI 0.60–0.89) and 9–11.9 months (OR 0.70, 95% CI 0.50–0.98). Other outcomes were similarly lower. Of note, only ∼15% of patients were controlled 6–9 months and 5% for 9–12 months annually. The report indicated that time-in-control is an important variable in a broad range of cardiovascular outcomes and that only ∼20% of patients were in the lower risk groups with BP controlled to less than 140/less than 90, 6 or more months annually. In newly diagnosed hypertensive patients, the current study indicates that time-to-control is a key, independent factor linked to all-cause mortality [1]. This report viewed together with TITRE report and other studies noted [2–6] is consistent with guidance that early and sustained BP control to less than 140/less than 90 is required to minimize hypertension-related events [7]. Given variability of BP in many clinical settings, most individuals and patient groups consistently controlled to less than 140/less than 90 will have mean clinic BP less than 130/less than 80 [8]. ACKNOWLEDGEMENTS Conflicts of interest In the past 3 years, B.M.E. has received royalties from UpToDate, research support from Medtronic and Quintiles, income as a consultant from AstraZeneca, Medtronic, and Valencia, and honoraria for lectures from Merck-Serono and Emcure.