Implications of Recent Clinical Trials and Hypertension Guidelines on Stroke and Future Cerebrovascular Research

Introduction

The decline in stroke mortality observed over the past 50 years has been attributed, t in part, to improved implementation of high blood pressure (BP) treatment and control strategies based on the most current evidence from clinical research studies and randomized controlled trials(RCTs).¹ The reduction in stroke risks coincides with the shift to lower systolic BP (SBP) distributions in the US adult population for all age groups.¹ However, critical clinical questions remain regarding the treatment, control, and prevention of high BP. New evidence from RCTs and meta-analyses^2–6 is expected to have an important positive impact on hypertension guidelines, clinical practice, and future research. Because stroke risk is substantially associated with BP levels and hypertension treatment and control, raised BP and stroke reduction is so heavily tied to BP control, stroke prevention is a key driving force for clinical practice decisions. As a component of the 2017 International Stroke Conference, the American Heart Association, American Stroke Association and World Hypertension League co-sponsored session focused on impact of recent hypertension studies, meta-analyses and new clinical guidelines on stroke risk reduction, and implications for future research.

Post-hoc analyses of stroke risks and reduction blood pressure treatment and control

The Prospective Studies Collaboration⁷ showed a log-linear relationship between BP and stroke declining with lower BP values right down to less than 120 mmHg systolic and less than 70 mmHg diastolic. Further, a meta-analysis of 147 RCTs of antihypertensive therapy the percentage reduction in stroke with BP reduction down to a mean of 110/70 mmHg regardless of their BP before treatment.⁸ Another systematic review in patients with diabetes reported a decrease of 13% in the risk of stroke for each 5 mm Hg reduction in SBP, and by 11.5% for each 2 mmHg reduction in diastolic BP (DBP).⁹ In another meta-analysis of 123 studies, Ettihad et al ⁴ provided support for lowering SBP to less than 130 mmHg. All of these reports suggest that there is no “J-shaped curve” at least at BP levels within these ranges.

However, all of these data were derived from post hoc analyses, usually from studies of the efficacy of antihypertensive drugs, and there were no convincing RCTs addressing the specific question of BP targets for the prevention of cardiovascular disease (CVD) events, including stroke, until the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Systolic Blood Pressure Intervention Trial (SPRINT).

Implications of ACCORD and SPRINT results and stroke outcomes

ACCORD ¹⁰ was l designed to evaluate the overall effects intensive BP lowering in patients with type 2 diabetes on CVD and stroke. The composite primary outcome included nonfatal stroke. The study randomized 4733 patients to intensive therapy, SBP target <120 mm Hg, or to standard therapy, SBP <140 mmHg. BP at each visit was measured using an automated measurement system (Model 907, Omron Healthcare). At each clinic visit BP was recorded as the mean of three measurements while patients were seated.

In ACCORD, the mean SBP after 1 year was 119.3 mmHg in the intensive-treatment group and 133.5 mmHg in the standard-treatment group. Equivalent values for SPRINT were: 121.4 mmHg in the intensive-treatment group and 136.2 mmHg in the standard-treatment group, for an average difference of 14.8 mmHg. In ACCORD during a mean follow-up of 4.7 years, there was no significant difference between the two groups with respect to the primary composite outcome or of most of its individual components, although there was a trend favoring the intensive treatment arm (suggesting that the study was underpowered). There was a significantly lower incidence of stroke in the intensive therapy group than in the standard therapy group (36, or 0.32% per year vs 62 or 0.53% per year; HR 0.59 (95%CI 0.39–0.89; P<0.01) (Table 1 and Figure 1). Since patients with prior stroke were not excluded from ACCORD, the stroke outcome in ACCORD could be regarded as relating to both primary and secondary prevention.

Table 1.

Comparison of data and stroke outcomes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Systolic Blood Pressure Intervention Trial (SPRINT) trials.

	Mean age - yr.	Body Mass Index	Years of Follow-up	Intensive Treatment N (%/yr)	Standard Treatment N (%/yr)	Hazard Ratio (95%CI)	P value
ACCORD	62.2±6.9	32.1±5.6	4.7 (mean)	36 (0.32)	62 (0.53)	0.59 (0.39–0.89)	<0.01
SPRINT	67.9±9.4	Not reported	3.2 (median)	62 (0.41)	70 (0.47)	0.89 (0.63–1.25)	0.19

Figure 1.

Results from Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showing the reduction in stroke risks with intensive hypertension treatment with the Kaplan-Meier curves for stroke starting to diverge at about 3.5 years. Figure generated from data form: The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–1585.

The design of SPRINT¹¹ was almost a mirror image of that of ACCORD. A total of 9361 adults with a SBP of 130–180 mm Hg and a high risk of CVD, were randomized to SBP target groups, <120 mm Hg and <140 mm Hg. The primary composite outcome was MI, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. As in ACCORD, BP at each visit was measured using an automated measurement system (Model 907, Omron Healthcare). The mean of three measurements was recorded. Thus, both ACCORD and SPRINT may have set a new standard for office BP measurement. Subjects with prior strokes were excluded from SRPINT. After 1 year, the mean SBP was 136.2 mmHg in the standard treatment group and 121.4 mmHg in the intensive treatment group, with an average difference of 14.8 mmHg. The study was stopped early after a median follow-up of 3.26 years, because the rate of the primary composite outcome was 25% lower in the intensive treatment group than the standard treatment group (hazard ratio with intensive treatment 0.75, 95% confidence interval 0.64 to 0.89; P<0.001). All-cause mortality was significantly reduced, by 27%. One unexpected finding was that the difference between the two groups was driven primarily by a decrease in heart failure and cardiovascular death, but there was no significant difference in stroke (Intensive treatment 0.41% per year, standard treatment 0.47% per year). Although not statistically significant, the hazard ratio for stroke with intensive treatment was 0.89, a decrease of 11 %.( Table 1). Because patients with prior stroke were excluded from SPRINT, the lower stroke rate reflects inclusion of a primary prevention patient sample.

In the elderly (≥75 years), there was a 28% lower incidence of stroke in the intensive-treatment group which was also not statistically significant (HR 0.72, 5% CI 0.43–1.21, P=0.22). ¹² This result does support lower BP targets in the elderly, although, in these patients, the BP should be lowered slowly and they should be closely monitored for any untoward effects including dizziness, syncope, any neurologic symptoms, angina, or worsening cardiac or renal function. Elderly persons are prone to isolated systolic hypertension and arterial stiffness. Thus, aggressive or substantial lowering of BP may result in the potential for loss of cerebral autoregulation as their autoregulatory curves are shifted to the right, and the possibility of borderzone brain infarcts associated in some with relative or absolute hypotension. Thus, in individual cases there may be a need to seek less aggressive BP treatment targets, especially if dizziness, syncope or neurologic or cardiac symptoms ensue or if there is development of renal dysfunction.

A reasonable conclusion from these studies is that there is now support for more intensive BP lowering in both diabetic and non-diabetic patients, and that a SBP target of <120 mmHg is a reasonable option for adults with high CVD risk This conclusion is also supported by a SPRINT sub-study demonstrating that patients with prediabetes derived a similar cardiovascular benefit from intensive BP lowering as those with normoglycemia.¹³

Responses to criticisms of SPRINT in consideration of stroke

While the SPRINT results are strong with high impact, there are several criticisms and questions that are frequently evoked by clinicians that have implications for stroke.

There was an unacceptable incidence of side-effects

These included an increased incidence of a ≥30% reduction in eGFR in SPRINT intensive compared to standard treatment participants without chronic kidney disease at baseline. However, even in those with chronic kidney disease at baseline the average difference in eGFR between groups was only about 3 ml/min/m ^2.14 An explanation, yet to be verified in a more detailed analysis of the renal data, is that subjects in the intensive group were more likely to be treated with blockers of the renin-angiotensin system, and at higher doses. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers dilate the efferent arterioles of the kidney, reducing glomerular filtration pressure and thus glomerular filtration rate, a benign hemodynamic effect. Also, as expected, hypotension (2.4% vs 1.4%) and syncope (2.3% vs.1.7%) were more frequent in the intensive vs. the standard treatment group, as was hyponatremia and hypokalemia (possibly related to more intensive diuretic dosing). ¹⁵ However, orthostatic hypotension was more common in the standard group (p = 0.13) and there was no significant difference in the incidence of orthostatic hypotension with symptoms. There was a significant difference in serious adverse events (SAEs; hospitalizations) associated with hypotension (the 2.4 vs. 1.4%) and syncope (2.3 vs. 1.7%) but no overall difference in SAEs between the two treatment groups.

I would not apply these findings to my elderly, frail patients

In a pre-specified sub-group analysis of SPRINT participants ≥75 years, the incidence of the primary outcome was significantly lower in the intensively treated group in the fit elderly, the less fit elderly and even in the frail elderly, ⁶ and also in those with diminished gait speed and mobility. ^{15, 16}

The absolute risk reduction is small

The rate of the primary outcome was 1.65% per year for the intensive group and 2.19% per year for the standard group, so the absolute risk reduction is “only” 0.54% per year. However, hypertension is such a common risk factor for stroke and CVD that the benefit of applying the SPRINT target to the population at large is substantial.¹⁷ It can be calculated that, in the United States alone, there would be 90,000 fewer cardiovascular events, 62,000 fewer deaths, and 10,100 fewer strokes, per year based on the SPRINT results.

There was no statistically significant benefit in reducing stroke

While true, but the stroke rates were: intensive treatment: 0.41% per year and standard treatment: 0.47% per year, with a hazard ratio of 89% and a relative risk reduction 11%. This, together with the ACCORD stroke data, with its 41% relative reduction, and the vast preponderance of the evidence supports aggressive BP reduction to prevent strokes.

Patients with prior stroke were excluded from SPRINT, so SPRINT tells us nothing about secondary stroke prevention

These patients were excluded as the Secondary Prevention of Small Subcortical Strokes (SPS3) trial¹⁸ was implemented, which included 3020 patients with MRI-defined symptomatic lacunar infarctions. Patients were randomized to a target SBP of 130–149 mmHg, or to less than 130 mmHg. At 1 year, mean SBP was 138 mm Hg (95% CI 137–139) in the higher-target group and 127 mmHg (95% CI 126–128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64–1·03, p=0·08), and disabling or fatal stroke (0·81, 0·53–1·23, p=0·32) with the lower target. The rate of intracerebral hemorrhage, however, was reduced significantly (0·37, 0·15–0·95, p=0·03). The authors concluded that although the reduction in total stroke was not statistically significant, the results support the conclusion that in patients with recent lacunar stroke, a SBP target of less than 130 mmHg is likely to be beneficial.

Why were the stroke outcomes in ACCORD and SPRINT so different?

The ACCORD Kaplan-Meier curves for stroke start to diverge at about 3.5 years. (Figure) SPRINT was stopped before that (median follow-up 3.26 years). So, a reasonable hypothesis is that the SPRINT 11% RRR for stroke might have increased to significant levels had the study been extended for a longer time period..

Watershed infarcts can occur due to hypoperfusion in patients with significant arterial stenosis in cervicocephalic arteries, and none of the trials assessed the presence/degree of arterial lesions. In (the Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial aggressive medical treatment alone with aggressive medical treatment and percutaneous transluminal angioplasty and stenting (PTAS) in patients with TIA or non-disabling stroke caused by stenosis of 70 to 99% of intracranial arteries, the target systolic blood press was < 140 mmHg for nondiabetics and < 130 mmHg for diabetics.¹⁹ Stroke recurrence was less frequent than in previous studies and this result contributed to change the paradigm of treatment in patients with large-artery intracranial atherosclerosis. Aggressive medical treatment included control of other risk factors and lifestyle changes, and it is not possible to determine which component of the treatment (BP target or other measures) played the most beneficial role on secondary stroke prevention. ) Still, the success of medical treatment decreased fears about risks of provoking strokes by treating hypertension to the chosen targets in patients with large-artery disease at risk of hypoperfusion. Whether a lower target (BP < 120 mmHg) can also be safely applied to all patients with large-artery stenosis remains unknown.

Recent meta-analyses of randomized clinical trials on intensive BP reduction and stroke prevention

Prediction models from the 1980s indicated that a 10 mmHg lower SBP would predict a 40% reduction in stroke risk with stroke risk reduced even with as little as a 2 mmHg SBP reduction.¹ These models were accurate with stroke mortality rates lowered with the shifts in SBP distribution in the US from 1960 to 2005.¹ On a population basis, therefore, every mmHg in BP lowering can be of potential clinical importance, especially in reducing stroke risk.

Recently, five meta-analyses have employed different analytical approaches comparing more versus less intense BP targets on the risk of stroke outcomes.^2,3,20,21,22 In each, the risk of stroke was significantly improved with more intense over less intense BP reduction. Xie et al.³ analyzed 19 randomized clinical trials (RCTs; not including SPRINT) in 44,989 participants during 3.8 years of follow up. BP levels in the more intensive BP group achieved 133/76 mmHg compared with 140/81 mmHg in the less intensive group. This BP difference resulted in a 22% risk reduction (RR) (P<0.001) for stroke in the more intensive over less intensive group. Thomopoulos et al.² analyzed 16 RCTs (including SPRINT) comparing more vs less intense blood pressure targets. The trials were stratified by achieved SBP. In all three tiers of achieved SBP reduction, there were significant reductions in RR (all P<0.001). The standardized stroke RR [95% confidence intervals (CI)] were 0.68 [0.60–0.79] for 140–149 vs ≥ 150 mmHg; 0.62 [0.51–0.76] for 130–139 vs ≥ 140 mmHg and 0.71 {0.61–0.84] for < 130 vs ≥ 130. Verdecchia et al.²⁰ employed a cumulative and sequential meta-analysis of 18 RCTs (including SPRINT) with random allocation of 53,405 participants to more vs. less intensive BP targets. Consistent with the results of the aforementioned studies, the more intense BP lowering strategy was associated with a significant reduction in the cumulative risk of stroke: odds ratio (OR) 0.802 [0.676–0.952]. Bangalore et al.²¹ performed a network meta-analysis involving 17 RCTs in 55,163 participants. There was a significant reduction in the risk of stroke with lower on-treatment SBP targets. SBP targets of < 120 and < 130 mmHg ranked as #1 and #2, respectively, as the most efficacious targets for the prevention of stroke, whereas the target of <120 mmHg ranked worst in terms of adverse events. Cluster analysis for combined efficacy and safety outcomes showed that a SBP target of < 130 mmHg achieved the best balance between efficacy and safety.²¹ Bundy et al employed a network meta-analysis to pool information from 44 clinical trials, providing substantial statistical power for randomized comparisons of SBP during treatment.²² The analyses demonstrated a reduction in risk of major CVD at lower levels of achieved SBP (e.g. SBP 120–124 was significantly better than 125–129 mm Hg). There were similar findings for stroke. Taken together, the evidence from these five meta-analyses suggests that SBP < 130 mmHg may be most clinically advantageous BP target in the prevention of stroke.

Implications of the Hypertension Guidelines on Stroke Risks

The first US national guideline for detection, evaluation and treatment of hypertension (JNC 1) was published in 1977.²³ Subsequently, updated JNC reports, as well as guidelines from national, regional and global organizations were developed for BP management. Although many of the core recommendations have been similar, considerably more attention has been paid to disagreements than similarities between different guidelines.²⁴ This has led to confusion for practitioners and the general public^25,26. Between 2013 and 2017, five clinical practice guidelines that specifically focused on BP management have been published.^27–31 Two of the five were US-based reports^28.31, while the other three were from Europe²⁷, Canada³⁰ and Australia²⁹. (Supplemental Table I) The European, Canadian and Australian guidelines reports were comprehensive documents that provided recommendations dealing with prevention, diagnosis, evaluation, and management of high BP.^{27, 29, 30,} In contrast, one of the US guidelines was restricted to recommendations related to pharmacological treatment questions in adults²⁸ and the other was restricted further to pharmacological treatment questions in adults ≥60 years.³¹ Although automated office BP (AOBP) measurements were recommended as the preferred means to assess level of BP in the Hypertension Canada report³⁰, all five of the guidelines based the diagnosis of hypertension on traditional office measurements with an average SBP ≥140 mm Hg or a diastolic BP (DBP) ≥90 mm Hg.

Use of CVD risk as a guide for pharmacological treatment of hypertension was first recommended in 1993.^32,33 The rationale is that treatment is unlikely to prevent CVD events in settings where events are likely to be infrequent. Specifically, the absolute benefit of drug treatment as a means to prevent CVD and stroke events or death is modest and the number needed to treat to prevent a CVD event or death is quite high in adults with a low risk for CVD^34,35. The JNC 5 guideline³⁶ suggested that target organ damage or multiple risk factors should influence the decision to initiate antihypertensive drug therapy. The importance of underlying CVD risk was further emphasized in the JNC 6 report³⁷. In contrast to JNC 5 and 6, the JNC 7 guideline³⁸ and the 2014 report from the panel members appointed to the Eight Joint National Committee (JNC 8 Panel)²⁸ provided recommendations for drug treatment of hypertension that were primarily based on level of BP, with indicators of CVD risk only playing an indirect role. The American College of Physicians (ACP) and American Academy of Family Physicians (AAFP), European Society of Hypertension (ESH) and European Society of Cardiology (ESC), Canadian Hypertension Education Program (CHEP) and the National Heart Foundation of Australia (NHFA) guidelines all emphasize the role of CVD risk in BP treatment decision-making.

The three comprehensive guideline reports provide recommendations for nonpharmacological interventions, with the 2016 CHEP guideline adding a recommendation for increased dietary potassium intake in those not at risk for hyperkalemia³⁰. The recommendation was based on meta-analyses that document a BP-lowering effect of increased potassium intake³⁹. This is an intervention that seems to be especially useful in those consuming a high intake of dietary sodium^40,41 and in Blacks⁴⁰. It also may reduce the risk of strokes⁴².

All five guidelines recommended use of either a diuretic, calcium channel blocker (CCB), angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for first-step monotherapy of hypertension, with further specification of class type in some of the reports. Use of a β-blocker for first-step monotherapy was also recommended in the ESH/ESC and CHEP guidelines but not in the JNC 8 Panel or NHFA reports. The ESH/ESC, CHEP and NHFA guidelines all endorse combination drug therapy as an alternative to monotherapy, especially in patients with a higher BP^27,30 or at high risk for CVD²⁷, but specifically recommend against concurrent use of an ACEI and ARB combination^29,30 or two drugs that block the renin-angiotensin system²⁷. There was considerable diversity regarding recommendations for drug choice in patients with a prior history of a stroke or transient ischemic attack, with an ACEI or diuretic being recommended in the CHEP guideline, any first-line drug in the NHFA guideline, no definitive recommendation in the ESH/ESC guideline (but an apparent preference for a CCB, diuretic or an ACEI-diuretic combination). Choice of antihypertensive medication for long-term management in stroke survivors was not addressed in the other two guidelines.

The 2017 Guidelines, sponsored by the American College of Cardiology/American Heart Association and nine other professional societies, represent some of the latest evidence-based recommendations with specific consideration of blood pressure reduction for lower stroke risks.^43,44 While the impact of these Guideline for the prevention, detection, evaluation and management of high BP has not been quantified, it would be expected that significant effects on stroke reduction will be found, similar to the previous robust recommendations.

Questions for Future Research related to Hypertension and Stroke Risks

During the past 50 years, enormous advances were made in the pharmacological treatment of hypertension.⁴⁵ Multiple trials demonstrated that treatment of hypertension consistently decreases stroke risk. Still, large gaps remain in the evidence-base of SBP targets for primary and secondary stroke prevention. Evidence specific for SBP targets for reduction of stroke risks has been limited to a few reports,^46,47 and the SPRINT results with the early ending, was unable to add critical information for stroke.¹² Further, SPRINT results did not contribute to define targets for secondary prevention because patients with stroke were excluded from the study.¹² The lack of significant stroke reduction has typically been explained by the design and statistical power of the study. The expected incidence of stroke was only 0.47% per year in SPRINT and few strokes (62 in the intensive treatment group and 70 in the standard treatment group) occurred during the trial at a median follow-up of 3.26 years.⁴⁸ The focus on evidence for BP targets for stroke remains a critical global need. ⁴⁹

The selection of subjects at high risk of cardiovascular events either by definition of clinical CVD or high estimated 10-year risk as inclusion criteria has advantages and drawbacks. This high-risk strategy can maximize absolute benefits or benefit-to-risk ratios and increase the probability of finding differences between groups in which rates of events are expected to be high, thus representing potential advantages considering that numbers of patients and durations of follow-up represent challenges for the design of clinical trials in stroke prevention. Also, this approach is consistent with a prevention paradigm that focuses on providing intensive clinical care for high-risk individuals.⁵⁰ However, there are disadvantages in the exclusion of subjects based on 10-year cardiovascular risk. Age is a strong predictor of 10-year risk, therefore middle-age or younger subjects considered to be at low or intermediate may be excluded from prevention trials in spite of a substantial lifetime risk.^51, This is particularly relevant for stroke prevention because hypertension may be undertreated in younger individuals. For instance, only 40.1% of US hypertensive individuals aged 20–39 years had their BP under control.⁵² Meta-analyses showed that intensive BP treatment was able to decrease stroke risk in groups at low, intermediate or high 10-year cardiovascular death risk,⁵² with mean achieved SBP targets (130.8 to 140.8 mmHg in the intensively-treated groups) consistent with intensive treatment in SPRINT.⁵³

Still, it remains to be determined whether intensive treatment of hypertensive patients regardless of cardiovascular risk can further decrease stroke without increasing serious adverse events, compared to standard treatment. In the HOPE-3 study,⁵⁴ subjects at intermediate cardiovascular risk but without stroke or other cardiovascular diseases were randomized to treatment with a fixed-dose combination of candesartan and hydrochlorotiazide or candesartan and placebo. The difference in stroke risk was not significant between the two groups after follow-up of 5.6 years. However, HOPE-3 was not able to determine whether more intensive treatment of hypertensive subjects decreases stroke risk because only 38% of the subjects included in the study were hypertensive at baseline, the difference attained in SBP between the two groups was small (6 mmHg) and the study did not apply a target-to-treatment approach. On the other hand, post-hoc analysis from the China Stroke Primary Prevention Trial⁵⁵ indicated that in subjects without stroke, an SBP goal of 120 to 130 mmHg was associated with a lower risk of stroke compared to targets of 130–140 or < 120 mmHg. Further trials are necessary to answer this question worldwide. An important point is that an SBP < 120 mmHg measured according to the unattended automated protocol employed in SPRINT may correspond to an SBP < 130–136 mmHg according to auscultatory methods used in other trials.⁵⁶

For secondary prevention, the ongoing Optimal Blood Pressure and Cholesterol Targets for Preventing Recurrent Stroke in Hypertensives (ESH-CHL-SHOT) is testing three different targets (< 120 mmHg, 125 to <135 mmHg and 135–145 mmHg) in patients with history of stroke or transient ischemic attack. In contrast to other treatment-to-target trials of hypertension, the primary outcome is recurrent fatal or nonfatal stroke.⁴⁸ Secondary outcomes include cognitive impairment and dementia, of major relevance considering the devastating effects of hypertension on cerebrovascular damage and the inconclusive evidence about effects of antihypertensive treatment on cognition.⁵⁷ Results of the SPRINT MIND and SPRINT MIND MRI substudies⁵⁸ may also provide valuable information about whether a more intensive BP target can prevent cognitive decline or subclinical brain lesions.

Finally, when trials aiming to decrease stroke risk are designed, absolute BP targets may not be the only relevant goals of treatment. Variability in BP, night-time SBP and other measures obtainable through ambulatory BP monitoring⁵⁹ may be of value for the prevention of stroke⁶⁰ or cognitive deterioration⁶¹ but optimal evidence-based targets for these measures are not yet available.

Implementing Hypertension Guidelines for the Reduction of Stroke Risks

Implementation of more intense BP control will require new approaches both by individual physicians and importantly by health systems throughout the world. Strategies will include improvement of lifestyle modification using behavioral and motivational strategies, addressing drug non-adherence, employment of team-based care, greater utilization of health information technology, including electronic health records and patient registries, and forming new connections for patients to their health care teams by telehealth. Great success has recently been demonstrated by Kaiser Permanente of Northern California, which utilized f these strategies to improve the control of hypertension from 44 to 90% over a 14 year period with a concomitant reduction in death from stroke by 42%.⁶²

Strategies to achieve BP control require medication nonadherence. Berra et al. have reported one-quarter of patients newly initiated on antihypertensive therapy fail to fill their initial prescription.⁶³ During the first year of treatment, the average patient has possession of antihypertensive medication only 50% of the time. Only one in 5 patients has sufficiently high adherence to achieve the benefits observed in RCTs. Thus, lack of adherence to antihypertensive drug therapy is often a major barrier to the achievement of target BP goals and consequently the prevention of stroke.

Methods for assessment of possible medication nonadherence can be divided into indirect (self-report: questionnaire, diary, interview; pill count: manual, electronic monitoring device and prescription registries) and direct (directly observed therapy and therapeutic drug monitoring) methods⁶⁴ Clarification of the optimal method(s) for detection and treatment of nonadherence to antihypertensive drugs is vital to the prevention of stroke in the future.

Summary and Conclusions

While stroke risks have been long recognized as associated with BP levels, recent trial results provide detailed evidence for the benefit of hypertension treatment and control.⁶⁵ Further, as stroke represents a particular global burden for many of the larger world populations including China, India and Brazil, high BP is at a critical point in time.⁶⁶ Thus, the implications of the new study results and subsequent recommendations based on the evidence can have significant impact.⁶⁷ The information presented as part of the ISC Session was timely and detailed and focused on the implications of the current study results building on the previous trials with a targeted interdisciplinary clinical audience. These data are particularly relevant given the recent report that the prior declines in stroke death rates have not continued in recent years, and the importance of strategically identifying opportunities for hypertension treatment and control.⁶⁸