How Low to Go With Glucose, Cholesterol, and Blood Pressure in Primary Prevention of CVD

Kimberly N. Hong, MD, MHSA; Valentin Fuster, MD; Robert S. Rosenson, MD; Clive Rosendorff, MD, PHD; Deepak L. Bhatt, MD, MPH


J Am Coll Cardiol. 2017;70(17):2171-21-85. 

In This Article


Although there is indisputable evidence that controlling blood pressure is associated with a reduction in CVD events, blood pressure targets, thresholds for beginning pharmacological treatment, and how different comorbidities factor into the management of an individual's blood pressure are controversial.[70]

When Should Antihypertensive Treatment be Initiated?

With the most recent Eighth Joint National Committee recommendations, HTN treatment is initiated at an SBP >140 mm Hg. However, based on observational data, CVD risk begins to accrue at lower values. A meta-analysis of prospective observational studies found a direct correlation between CVD deaths and SBP down to a threshold of 115 mm Hg.[71] As many as 39% of male and 23% of female patients have an SBP between 130 and 139 mm Hg and are at increased risk of developing HTN. An analysis using the Framingham cohort stratified individuals by their baseline blood pressure into the following groups: optimal (<120 mm Hg), normal (120 to 129 mm Hg), and high-normal (130 to 139 mm Hg). CVD risk, adjusted for diabetic status, cholesterol, age, sex, body mass index, and smoking status, was higher in patients with high-normal versus optimal blood pressures.[72] Based on these data, 2 randomized trials, PHARAO (Prevention of Hypertension With the Angiotensin-Converting Enzyme Inhibitor Ramipril in Patients With High-Normal Blood Pressure) and TROPHY (TRial Of Preventing HYpertension), attempted to answer whether pharmacological intervention should be initiated at SBP >130 mm Hg.[73,74] Both of these trials showed that initiation of pharmacological agents delayed the onset of HTN. However, because these trials were not powered to assess differences in CVD event rates, no reduction in CVD events was found.[74,75] Furthermore, although treatment was not associated with increased adverse events, ramipril was associated with more cough (4.8% vs. 0.4%).[74,75] Thus, to date, there are minimal data to support treating pre-HTN.

In the HOPE-3 trial, the HTN arm received a fixed-dose combination pill of candesartan and hydrochlorothiazide.[76] The design of this trial was novel, because rather than categorizing individuals by their risk factors, it evaluated the effectiveness of risk factor–modifying treatments on individuals who had an increased risk of developing CVD. Thus, strict inclusion criteria based on definitions for hyperlipidemia and HTN were not used. Furthermore, individuals with a baseline diagnosis of HTN could be included as long as they were not previously on a thiazide, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker.

At the end of the study, the mean decrease in blood pressure was 10 mm Hg in the treatment group versus 4 mm Hg in the control group (p < 0.05). There was no difference in primary or secondary endpoints. Importantly, a subgroup analysis that stratified baseline blood pressure into tertiles (≤131 mm Hg, 132 to 143 mm Hg, and >143 mm Hg) found a benefit in the primary outcome in the >143 mm Hg group. Of note, there was separation of the Kaplan-Meier curves for stroke, MI, and revascularization with time, which suggests that these differences may become significant with longer follow-up.[76] Although there were no differences in the safety outcomes, there was an increased incidence of symptomatic hypotension, dizziness, and lightheadedness in the treatment group. This trial has important clinical implications because it supports current guidelines that individuals without HTN who are at intermediate CVD risk should not be pharmacologically treated.[76] However, given the increased relative risk of CVD events based on epidemiological studies, it is reasonable to encourage lifestyle changes that include exercise, sodium restriction, and nutritional counseling.

How Low Should we Go?

There is significant debate over what the SBP treatment target should be. Much of this arises from the J-curve phenomenon in CVD outcomes, excluding stroke, described in observational data and randomized controlled trials evaluating HTN therapies.[77–80] The mechanisms for this relationship include the presence of atherosclerotic plaques and decreased perfusion pressures distally. These data are primarily from individuals with HTN, DM, or pre-existing CVD.[81,82] Thus, the presence of this phenomenon in a primary prevention cohort is less clear. Prior to SPRINT (Systolic Blood Pressure Intervention Trial), few trials included a significant number of individuals without a prior history of CVD.

One of the first trials that was designed to assess the J-curve phenomenon was the HOT (Hypertension Optimal Treatment) trial, which randomized individuals with HTN to treatment groups of diastolic blood pressure ≤90, ≤85, or ≤80 mm Hg.[83] The mean age of patients in this trial was 61 years, and 1.5% had pre-existing CVD. This trial found no increase in CVD events in the lower diastolic blood pressure group, but also did not find a difference in CVD risk reduction.[83]

VALUE (Valsartan Antihypertensive Long-Term Use Evaluation) was a randomized controlled trial that included individuals age ≥50 years with a high CVD risk (determined by diabetes mellitus, current smoking, total cholesterol, left ventricular hypertrophy, proteinuria, or raised serum creatinine) or with coronary or peripheral artery disease. The treatment arms in the trial were valsartan and amlodipine with a target SBP <140 mm Hg. The mean age of the participants was 67 years, and 46% of them had pre-existing CAD.[84] A post hoc analysis that stratified by baseline CAD showed no J-curve. However, although no increase in CVD risk was found, there was similarly no additional benefit conferred by obtaining an SBP <130 mm Hg.[85]

In the ACCORD study, participants with type 2 DM were randomly assigned to intensive therapy (blood pressure target <120 mm Hg) versus standard therapy (blood pressure target <140 mm Hg). The primary composite outcome was nonfatal MI, nonfatal stroke, or death from CVD causes. At 1 year, the mean SBP in each group was 119.3 and 133.5 mm Hg, respectively. However, there was no difference in the primary outcome between groups.[86] The authors comment that the event rate in the standard group was almost 50% lower than the expected rate, suggesting that the study was underpowered. Additionally, the diverging Kaplan-Meier curves suggest that the outcomes may have become significant if there had been more subjects or if the study had continued for a longer period.[87]

SPRINT was a randomized controlled trial that also compared an intensive blood pressure treatment strategy (SBP <120 mm Hg) to a standard blood pressure treatment strategy (SBP <140 mm Hg). Inclusion criteria for the trial were age ≥50 years, an SBP between 130 and 180 mm Hg, and categorized as having an increased CVD risk defined as: clinical or subclinical CVD (Table 3), chronic kidney disease with an estimated glomerular filtration rate 20 to 60 ml/m/1.73 m2, a 10-year CVD risk ≥15%, or age ≥75 years. Of note, individuals with prior stroke or DM were excluded.[87]

The primary outcome was a composite outcome of MI, acute coronary syndrome, stroke, acute decompensated heart failure, or CVD death. Secondary outcomes included the individual components of the composite, as well as death from any cause and the composite of the primary outcome with death from any cause. Safety outcomes included worsening kidney function.[87]

Study participants were randomized between 2010 and 2013. Median follow up was 3.26 years before the trial was ended early because of the primary outcome benefit seen in the intensive-treatment group. The mean age in the trial was 68 years; 17% of the trial participants had clinical CVD, which included peripheral artery disease; 10% were not on antihypertensive treatment at baseline, and 61% had a Framingham risk score ≥15%. The primary composite outcome rate was 1.65%/year in the intensive-treatment group compared with 2.19%/year in the standard group, which translated to a relative risk reduction of 25% and an absolute risk reduction of 0.54%/year. The composite endpoint was driven by the heart failure outcome and CVD deaths. Interestingly, in terms of secondary endpoints, there were no significant differences in rates of MIs, acute coronary syndrome, or stroke. Some considerations that affect interpretation include the early termination of the trial and its effects on longer-term outcomes, as well as the high percentage of individuals already tolerating a multidrug regimen (mean number of antihypertensive agents at baseline was 1.8).[87]

Although there were no differences in the renal safety outcomes in those with chronic kidney disease at randomization, in those without chronic kidney disease, individuals in the intensive-treatment group compared with the standard-treatment group had a ≥30% reduction in GFR (HR: 3.49; 95% confidence interval: 2.44 to 5.10). As expected, there were more serious adverse events in the intensive-than standard-treatment group (p < 0.001), which included hypotension, syncope, electrolyte abnormalities, and acute kidney injury/failure.[87]

The aforementioned trials suggest that in appropriately selected individuals, lower SBP will reduce CVD events and mortality without increasing MIs. A recent meta-analysis that stratified groups by baseline SBP found a similar decrease in CVD events, CAD, stroke, heart failure, and all-cause mortality across all SBP groups, including the lowest (<130 mm Hg). Analysis stratified by presence of baseline CAD did not change these findings.[70]

Even with this evidence, it is important to consider the potential adverse effects of tight blood pressure control such as syncope, dizziness, and renal injury on patient adherence. An interesting meta-analysis calculated a risk–benefit ratio of antihypertensive treatment that used permanent discontinuation of antihypertensive treatment as a proxy for a significant adverse event.[88] This meta-analysis found that for incremental reductions in SBP below 130 mm Hg, the relative risk of permanent discontinuations increased disproportionately to any additional benefit gained from a CVD risk-reduction perspective. This suggests that although there may still be an overall benefit to lower SBP, the cost of doing so in terms of medication discontinuation may not be worth it. With respect to SPRINT, it is important to note that the method used for SBP measurement, an average of three automatic blood pressure readings taken in a quiet room after being seated alone, was unlike that used in other trials and is different from real world practice. Thus, the SBP readings reported in SPRINT could have been ~5 to 10 mm Hg higher if measured by a manual device, while talking, or in a public nonquiet room.[2] Viewed in that light, the SBP targets in SPRINT are only slightly lower than what guidelines currently recommend.