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Hypertension: A Risk Factor for Stroke
  JOHTN
REVIEW ARTICLE
Hypertension: A Risk Factor for Stroke
Sunil Pradhan, Anirudh Rao Deshmukh, Robin Bansal, Ananya Das
Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Address for correspondence: Sunil Pradhan Professor, Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh,India
Received: 12-11-2017; Accepted: 20-12-2017
 
ABSTRACT
Stroke is one of the major causes of morbidity and mortality, especially in low- and middle-income countries, and its incidence isincreasing in view of changing demographics and increasing prevalence of its risk factors
Keywords: Hypertensive agents, perindopril , Epidemiology
How to cite this article: Pradhan S, Deshmukh AR, Bansal R,Das A. Hypertension: A risk factor for stroke. Hypertens2018;4(1): 31-35.
Source of support: Nil
Conflict of interest: None
 
 

Epidemiology of Stroke In India

Stroke is one of the major causes of morbidity and mortality,especially in low- and middle-income countries, and its incidenceis increasing in view of changing demographics and increasingprevalence of its risk factors. In 2012, India stroke factsheet wasupdated and the age-adjusted prevalence of stroke was estimatedto be around 84/100.000-264/100.000 in rural areas and334/100,000-424/100,000 in urban areas.[1] Crude prevalenceof stroke in a study done in Kolkata from 1998 to 1999 wasestimated to be around 147/100.000. Comparing these twostudies gives us an idea of the increasing burden of stroke in ourpopulation, especially in urban areas. There is a huge variation of147-999/100,000 across communities all over India.

Several risk factors have been identified including diet,diabetes, exercise level, smoking, lipids, and waist-hip ratio.Among the risk factors for stroke, hypertension has been seen tobe the most important.

Hypertension is the most important and the most prevalentmodifiable risk factor for ischemic stroke, and antihypertensivetreatment is of paramount importance to reduce the incidenceof stroke mortality and morbidity. Hypertension is the mostimportant risk factor, especially in first-ever ischemic stroke.It has been estimated that around 54% of strokes in low- andmiddle-income countries are caused by hypertension. The riskof stroke is positively associated with hypertension >115/75in a log-linear fashion with a steeper association seen withhemorrhagic stroke.[2-6] A summary of seven studies assigning arelative risk (RR) of 1 for borderline or mild HT determined the RR to be about 0.5 at a blood pressure (BP) of 136/84 mmHgand about 0.35 at a BP of 123/76 mmHg.[7] According to thissummary, the risk of stroke increased 10-fold from the lowest tohighest BP level.

 
A positive correlation has been found between hypertensionand hemorrhagic strokes in a systemic review[8] (14 studies:11 - case-control and 3 - cohort studies). The overall odds ratioof hemorrhagic strokes among hypertensive patients was 3.68.Leppala et al.[9] showed an adjusted RR (RR adjusted) of 2.20for systolic blood pressure (SBP) of 140-159 mmHg and 3.78for ≥160 mmHg compared with ≤139 mmHg. In another study,Suh[10] et al. found an RR of 2.2 for high normal BP, 5.3 for Stage1 hypertension, 10.4 for Stage 2 hypertension, and 33 for Stage3 hypertension. These two cohort studies demonstrated thatthe higher the degree of hypertension, the higher is the risk ofdeveloping ICH.

In interstroke study[11] done in 32 countries, hypertension(defined as self-reported or ≥ 140/90 mm of Hg) was seen asthe most important target for stroke prevention (populationattributable risk [PAR] ranging from 41.3 to 43.7 in ischemicstroke and 25.2 to 56.4 in hemorrhagic stroke in all regions). Incomparison, smoking, waist-hip ratio, diet, diabetes, and heartdisease had PAR of 12.4, 18.6, 23.2, 3.9, and 9.1, respectively[Table 1]. Hypertension was shown to be equally importantin both young (< 55 years) and old age groups and in men andwomen. This shows that large burden of stroke can be preventedby controlling blood pressure of the target population. A studyfrom Taiwan showed that patients with hypertension had 2.7-fold risk of having ischemic stroke,[12] next only to atrialfibrillation and ischemic heart disease. This study also showedthat hypertension was more strongly associated with intracranialbleed than ischemic stroke.

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Table 1: Hypertension analysis due to various parameters
Hypertension: A risk factor for stroke

BP Variability

There is enough evidence that BP variability is an independentrisk factor for stroke. Rothwell et al. reported that, in treatedhypertensive patients, visit-to-visit SBP variability was associatedwith a higher risk for ischemic than hemorrhagic stroke.[13]Moreover, there is evidence that BP variability even in patientswith normal BP is an independent risk factor for stroke.

Gender-specific Risk

It has been shown that women have a higher incidence of strokeaccounting for 60% of new strokes. This could be explained byhigher prevalence of hypertension in older women, higher lifeexpectancy in women, and loss of cardiovascular protectiveeffect in post-menopausal period. In a meta-analysis, it was seenthat woman with hypertension had a higher risk of stroke thanhypertensive men. This was especially true in the older age group.It was seen that when diastolic blood pressure (DBP) was higherthan 100 mmHg (compared with DBP ≤ 100 mmHg), womenhad a higher RR for ischemic stroke than men (multivariateadjustedRR for women: 2.5 and for men: 1.9).[14] Women were ata higher risk of ischemic stroke on stopping the antihypertensivemedication, when they are on post-menopausal hormonetherapy and when the hypertension is mild as compared to men.However, Tanizaki et al.[15] observed that when BP was increasedby 20 mmHg, there is a similar increase in the risk of stroke inboth men and women (42% and 45%), respectively.

Hypertension in Very Old

Stroke is more common in very old (>80 years) people.Hypertension is a major risk factor for stroke in youngerpopulation, but some population-based cohort studies didnot show any association between hypertension and incidentstroke in the very old age group. This difference could be dueto the physiological, pathological, and social differences betweenthese two groups. Hence, it is not right to apply the results fromyounger population to the very old age group. A populationbasedcohort study conducted by Hornsten et al.[16] where the incidence of stroke was 33.8/1000 person-years observed thatSBP (≥160), DBP (≥90), and mean arterial pressure (MAP)were independently and linearly associated with incidentstroke. Hypertension in the Very Elderly Trial (HYVET),[17] therandomized controlled "HYVET," and later a meta-analysis[18]which included HYVET found that antihypertensive therapyreduced stroke incidence and mortality even in very old people.

 
Secondary Prevention

Epidemiological studies have shown that reduction of SBP by10 mmHg reduces the incidence of stroke by one third in patientsbetween 60 and 79 years of age. Even a 5 mm of Hg drop in SBPis associated with 14% decreased risk in stroke mortality.[19] InACCORD trial 4733 patients were randomized to < 120 mmHg(intensive group) and 120-139 (standard group). After 4.7 yearsof mean follow-up, it was seen that stroke incidence and mortalitywere significantly less in the intensive group. There is mountingevidence that magnitude of BP lowering was more importantthan the antihypertensives used.[20]

The perindopril protection against recurrent stroke study(PROGRESS)[21] was designed to determine the role of bloodpressure lowering in both hypertensive and non-hypertensivepatients in secondary prevention of stroke. A total of 6105 patientswere included from various countries and randomized intoactive treatment (perindopril 4 mg and/or indapamide 1.25 mg)and placebo group. 307 (10%) persons in the active treatmentgroup suffered a stroke, compared with 420 (14%) in the placebo(RR reduction 28% [95% confidence interval (CI) 17-38],P < 0.0001). Active treatment also reduced the risk of totalmajor vascular events. There were similar reductions in the riskof stroke in hypertensive and non-hypertensive subgroups (all P< 0.01). Combination therapy with perindopril plus indapamidereduced blood pressure by 12/5 mmHg and stroke risk by 43%.Single-drug therapy reduced blood pressure by 5/3 mmHg andproduced no discernable reduction in the risk of stroke.

In Profess[22] trial, telmisartan 80 mg once daily was comparedwith placebo for secondary stroke prevention, but no significantdifference was seen among the groups. However, a post hocexploratory analysis showed lower rates of recurrent strokes intelmisartan group after 6 months. Similar lowering of the riskof stroke after 6 months was also seen in PROGRESS and hopetrial. Shorter duration of stroke onset, lower baseline BP, andlesser degree of blood pressure reduction in Profess trial couldbe the reason for insignificant results of this trial as comparedto PROGRESS trial. Moreover, even in PROGRESS trial,monotherapy with perindopril showed non-significant benefit,indicating that higher BP reduction is needed for any meaningfulbenefit and that combination therapy is more beneficial thanmonotherapy.

A comparative review between telmisartan and perindoprilconcluded that both ARB and ACE inhibitors showed beneficialeffects in secondary stroke prevention. However, most of theevidence for perindopril comes from studies done in patients with pre-existing hypertension, whereas the effects of telmisartanwere studied in non-hypertensive patients.[23] The 2014 AmericanStroke Association (ASA)/American Heart Association (AHA)guidelines recommend the use of ACE inhibitors with a diureticas the first-line antihypertensive in secondary prevention ofstroke. However, ASA/AHA did not take into account theaccomplish trial. Accomplish[24] trial randomized hypertensivepatients into two groups with benazepril plus either amlodipineor hydrochlorothiazide. Stroke was a secondary endpoint alongwith non-fatal myocardial infarction. The group with amlodipinehad a significant reduction of the incidence of secondaryendpoints as compared to hydrochlorothiazide group (5.0 vs.6.3). Around 13% of patients in this trial had a prior historyof stroke. Hence, some people recommend amlodipine incombination with ACE/ARB in place of a diuretic.

 
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The guidelines for the prevention of recurrent stroke andtransient ischemic attack (TIA) issued in 2017 by the AmericanCollege of Cardiology(ACC)/AHA recommend the initiationof blood pressure therapy for previously untreated patientswith ischemic stroke or TIA who, after the first 3 days, have anestablished blood pressure of ≥140 mmHg systolic or ≥90 mmHgdiastolic (or ≥130 mmHg systolic or ≥80 mmHg diastolic inpatients with lacunar stroke). The guidelines also recommendresumption of blood pressure therapy for previously treatedpatients with known hypertension and who are beyond the first3 days after stroke onset. They suggest < 130/< 80 mmHg as areasonable goal in all patients.

Management of Hypertension in Acute Stroke

One of the important issues in today's clinical practice is themanagement of BP in a patient with acute stroke. The generalhypothesis is that, during an acute stroke, cerebral autoregulationmechanism increases systemic BP to overcome decreased bloodflow to the ischemic penumbra region. This has also beenfrequently observed in acute ischemic stroke patients

However, the question is at what level of BP shouldantihypertensives be considered and when. Two trials(COSSACS[25] and ENOS[26]) which recruited 2800 patientswithin 48 h of stroke temporarily stopping antihypertensivesdid not show any benefit in functional outcome. Similarly,two meta-analysis[27,28] conducted in 2014 did not show anydifference in 30-day mortality when antihypertensives werewithheld in the acute period. However, these results have to beanalyzed carefully as most of these trials included patient withhemorrhagic stroke. Moreover, some of these trials recruitedpatients after 30-48 h, which makes these results difficult toapply to patients who present within 24 h. On the contrary, aBrazilian[29] observational study showed OR 1.9 per 10% SBPreduction. Similarly, an Austrian[30] study observed an OR of 3.8for a >25% DBP reduction. These studies are indicative of theharms of reducing BP in acute ischemic stroke.

International stroke trial[31] which recruited 17,398 patientsobserved a U-shaped association between BP and morbidity.

 
Patients with BP >200 had more new ischemic strokes, whereaspatients with BP < 120 had more deaths due to coronaryheart disease. Hence, in patients of acute stroke who are notcandidates for thrombolysis, BP lowering agents should not bestarted unless the BP is extremely high (>220/120). In somespecial cases where there is evidence of acute ischemic heartdisease, aortic dissection, pre-eclampsia/eclampsia, heart failure,and hypertensive encephalopathy, BP can be lowered by 15% infirst 24 h. Thrombolysis is considered a special circumstance,and in these patients, the BP should be lowered below 185/110before thrombolysis and maintained at or below 180/105 for atleast 24 h after thrombolysis. The preferred regimen for acute BPreduction in this setting is labetalol 10-20 mg, given IV over 1 to2 min (the dose may be repeated 1 more time). If SBP remainselevated to >180-230 mmHg or diastolic BP >105-120 mmHg,then labetalol 10 mg IV is followed by continuous infusion2-8 mg/min.[32] Nicardipine may be considered as an alternativechoice.

It is reasonable to restart the antihypertensive duringhospitalization and 7-14 days later (if there is evidence of largevessel narrowing) after acute ischemic stroke. Evidence of largevessel narrowing needs a slower reduction of BP, and hence, itis mandatory to rule out the same before starting or restartingantihypertensives in patients with BP >140/90.

In patient with hemorrhagic stroke, pathophysiology differsas the decision is between benefits of maintaining MAP toavoid cerebral hypoperfusion and reducing BP to preventhematoma extension/re-bleed. The presence of hypertension isassociated with hematoma expansion which may lead to earlyneurological deterioration in patients with ICH.[33] Cappellariet al.[34] showed that significant hematoma expansion occurredin about 45% of hypertensive patients, as compared with only19% of amyloid angiopathy-related ICH patients (odds ratio:3.081, P = 0.004). This makes lowering BP in acute hemorrhagicstroke more beneficial in reducing morbidity and mortality.This is in contrast to acute ischemic stroke, where BP loweringis not considered in the acute phase. This is because lowering ofBP may reduce cerebral perfusion pressure, leading to furtherischemia and brain damage in patients with acute ischemicstroke.

Limited clinical trial data are available for decision-makingin this regard. In a recent study, INERACT 2[35] trial recruited2839 patients within 6 h of symptom onset and randomizedthem to intensive group (< 140) and standard group (< 180).The intensive group showed better outcomes measured using amodified ranking scale. Recently concluded ATACH II[36] trialdid not show similar results. They recruited 1000 candidates andrandomly assigned them to intensive group (SBP 110-139) andstandard group (SBP 140-179). The mean blood pressures atpresentation in the emergency were 200 ± 27.1 and 200 ± 26.9,respectively. Primary outcomes of death and disability were seenin 38.7% in intensive group and 37.7% in standard group. Seriousadverse events occurring within 72 h were also similar in boththe groups. Based on the findings of INTERACT 2 trial, someguidelines[37] have been formed:

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  • For patients with SBP >200 mmHg or MAP >150 mmHg,consider aggressive reduction of blood pressure withcontinuous intravenous infusion of medication up to a targetof 140 mmHg SBP.
  • For patients with SBP >180 mmHg or MAP >130 mmHg andevidence or suspicion of elevated ICP, consider monitoringICP and reducing blood pressure using intermittent orcontinuous intravenous medication to keep cerebralperfusion pressure in the range of 61-80 mmHg.
  • For patients with SBP >180 mmHg or MAP >130 mmHg andno evidence or suspicion of elevated ICP, consider a modestreduction of blood pressure with a target MAP of 110 mmHgor target blood pressure of 160/90 mmHg.

Intravenous labetalol, nicardipine, and enalapril arerecommended for acute lowering of BP. Nitroglycerine andnitroprusside are second-line drugs as they have a theoreticalrisk of raised intracranial pressure. Rapidly acting nifedipinepreparations are contraindicated due to unpredictable fall in BP.

High risk of recurrence is noted in patients with hypertensiveICH. An observational single-center study[38] from Bostonwhich recruited 1145 patients of ICH with median follow-upof 36.8 months showed 102 recurrent ICH events among 505survivors of lobar ICH and 44 recurrent ICH events among640 survivors of non-lobar ICH. Inadequate BP control wasassociated with higher risk of recurrence of both lobar ICH(Hazard ratio [HR], 3.53 [95% CI, 1.65-7.54]) and non-lobarICH (HR, 4.23 [95% CI, 1.02-17.52]). Therefore, bloodpressure control has to be more strict and aggressive in patientswith the ICH. As per the guidelines of the AHA/ASA, SBPshould be kept < 130 mmHg after ICH, to reduce the risk of ICHrecurrence. SPS3, a multicenter international trial, showed thatintracerebral hemorrhage was reduced by 63% in those assignedto the lower target group (SBP < 130 mmHg) (HR 0.37 95% CI,0.14, 0.89, P = 0.03).

Hypertension is one of the most important risk factors for bothischemic and hemorrhagic strokes, and BP control is major stepin the prevention of stroke. ACE/ARB in combination withamlodipine and diuretics is of proven benefit in reducing BP andpreventing stroke. Acute BP reduction is harmful in ischemicstroke as it causes reduction of cerebral blood flow and furtherischemia. Therefore, attempts should not be made to normalizeBP gradually after ischemic stroke. In hemorrhagic stroke, acuteBP reduction helps in preventing extension of stroke, and hence,it is beneficial to use antihypertensives in acute bleed.

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