Hypertension and CVADr PS Deb MD, DMDirector Neurology Guwahati NeurologicalResearch Center, AssamHypertensionCVAHypertension
Hypertension and Stroke (WHO 2013)Hypertension causes 10%death in India• 51% death due to CVA• 45% due to CADStroke >25 years• 34% men• 32% womenPreventable by Rx• 35-45% Stroke• 25% CAD
Diastolic BP as Risk Factor of Stroke (< 1990)Eastern Stroke and CoronaryHeart Disease CollaborativeResearch Group• Diastolic BP 110 mmHg had13times risk of stroke as comparedto <79 mmHg0102030405060Stroke PreventionMacMohanStrokePrevention
Systolic BP as Risk factor for Stroke (>1990)Systolic BP was more strongly correlated with 12-year risk of strokemortality than diastolic BP in Framingham Heart StudyProspective population based Copenhagen City Heart study alsoreported systolic BP is a better predictor of stroke than diastolicAsia Pacific Cohort Studies Collaboration analyzing 37 cohort studiesreported a continuous, log-linear association between systolic BP andrisk of stroke down at least 115 mmHg.After a 10 mmHg decrease in systolic BP was associated with a 41%lower risk of stroke in Asia and a 30% in Australia
Age and Stroke with HypertensionElevated BP and risk of stroke is weakerin older age compared to middle ageThe Asia Pacific Cohort StudiesCollaboration (APCSC)Treating BP is still important due toincreased incidence of stroke with aging.0102030405060Stroke after 10mmHgDecrease of Systolic BPStrokePrevention
Pathogenesis of Stroke due to Hypertension1. Large vessel Atherosclerosis2. Medium vessel Arteriosclerosis3. Small Vessel Lipohyalanosis4. Cardioembolic stroke
Dys-autoregulation after Ischemic StrokeBrainstem strokeLarge HemisphericstrokeSubcortical stroke
Blood Pressure in Acute Ischemic StrokeSystolic blood pressure on arrival at Emergency• >139 mm Hg in 77%• >184 mm Hg in 15%.The blood pressure is often higher in acute stroke patients witha history of hypertensionBlood pressure decreases spontaneously within 90 minutes afteronset
BP control in Acute Ischemic StrokeIs lowering ofBP harmful?YesIs raising BPbeneficial?YesNoNoWhat class ofdrug?CC BlockerAB BlockerVasodilators
Is lowering BP is harmful? YesAutoregulation is defective in acute ischemia but it is timedependent.Oxygen extraction compensate to a pointBP control hamper perfusion of penumbra regionLowering BP below >10-15% is potentially harmfulHypertensive patient shows more significant decrease in MBPafter induced hypotension than hypertension
Oral Nimodipine in acute ischemic strokeA placebo-controlled randomized trial tested oral Nimodipinestarting within 48 hours after ischemic stroke onset in 350patients.The systolic and diastolic blood pressures were bothsignificantly lower in the Nimodipine group.Functional outcome at 3 months was similar in the 2 treatmentgroups, but mortality was significantly higher in theNimodipine group
Intravenous Nimodipine West European StrokeTrial (INWEST)Nimodipine as cytoprotective therapy within 24 hours after ischemicstroke onset and found complications related to blood pressureloweringDecrease in blood pressure was associated with intravenousNimodipine therapy and worse clinical outcome at 21 days.A decrease in diastolic blood pressure >10 mm Hg, but not in thesystolic pressure, was significantly associated with worse outcome
Candesartan in Acute StrokeAn efficacy trial (n=2004) of candesartan showed amean blood pressure reduction of 7/5 mm Hg at day 7Favorable outcomes at 6 months, were less likely withcandesartan than with placebo.
The Continue or Stop Post-Stroke AntihypertensivesCollaborative Study (COSSACS)Patients were enrolled within 48 hours of strokeonset and the last dose of antihypertensivemedication and were maintained in the 2 treatmentarms for 2 weeks.The study was terminated prematurely;however, continuation of antihypertensivemedications did not reduce 2-week mortality ormorbidity and was not associated with 6-monthmortality or cardiovascular event rates.
Is lowering BP in AIS harmful? NoDefective autoregulation may not be present in all patientsIschemic penumbra may not be present in all patientsClinical experience indicates that many patients tolerates gentletreatment of high BPNatural history studies demonstrate no deleterious effects oflowering BPHigh BP at onset has poor prognosis
Hypertension during acute ischemic strokeExtreme hypertension -> Encephalopathy, Cardiaccomplication, renal insufficiencyModerate arterial hypertension during acute ischemic stroke mightbe advantageous by improving cerebral perfusion of the ischemictissueIt might be detrimental by exacerbating edema and hemorrhagictransformation of the ischemic tissue
Candesartan in Acute StrokeStarting an average of 30 hours after ischemic stroke onsetin 342 patients with elevated blood pressure.Blood pressure and the Barthel index score at 3 monthswere similar in the 2 study groups,Patients who received the active drug had significantlylower mortality and fewer vascular events at 12 months.
Is Raising Blood Pressure in Acute IschemicStroke Beneficial? YesSmall pilot trials have carefullyraised the blood pressure in acuteischemic stroke patients withoutapparent complications.Severe intracranial atherosclerosisor stenosis may require BPelevation to maintain ICcirculation
Is Raising Blood Pressure in Acute IschemicStroke Beneficial? NoU shaped relation betweenadmission BP and outcomeElevated in-hospital blood pressureduring acute ischemic stroke hasbeen associated with worse clinicaloutcomes in a more linear fashion.
Other problem of raising BPIncrease risk of ICH after lytic therapyMay increase amount and formation of cerebral edemaA 12% increase in terms of size of infarction.May adversely affect cardiac function
Optimal BP during acute ischemic strokeExtreme arterial hypotension is clearly detrimental, becauseit decreases perfusion to multiple organs, especially theischemic brain, exacerbating the ischemic injury.An ideal blood pressure range has not yet been scientificallydetermined for individual patient.An ideal blood pressure range during acute ischemic strokewill depend on the stroke subtype and other patient specificco-morbidities.
Recommendation (AHA 2013)1. Not for thrombolysis > 220/120 mmHg,2. For Thrombolysis >185/100 mmHg3. Severe cardiac failure, Aortic dissection, Hypertensiveencephalopathy4. Cautious blood pressure lowering when (IVLabetalol, IV Enalepril, Nitrendepine) avoid venodilators
When to Temporary discontinuation of AHT?Because swallowing is often impaired, andresponses to the medications may be lesspredictable during the acute stress.
When to Re-start Antihypertensive TherapyAfter the initial 24 hours from stroke onset inmost patients.Individualize such therapy based on relevant co-morbidities, ability to swallow.
How to treat Hypertension in ICH?When should we treat HypertensionWhat is the target mean arterial pressure for patients withintracerebral hemorrhage (ICH)?Do we want to be aggressive or conservative?What should first-line therapy be: beta blockers or calcium-channel blockers?What should the duration of intravenous (IV) therapy be: 24hours or 72 hours?
Primary aim1. Early intensive blood pressure (BP) lowering (target of<140 mmHg systolic) as compared to the2. Guideline-recommended ‘standard’ control of BP(target of <180 mmHg systolic) improves3. Survival free of major disability in acute spontaneousintracerebral haemorrhage (ICH)Standardised treatment protocols – locally availableintravenous (IV) BP lowering agents of physician’s choice33
Protocol schema: from INTERACT1 (Lancet Neurol 2008)and (Int J Stroke 2010)Acute spontaneous ICH confirmed by CT/MRIDefinite time of onset within 6 hoursSystolic BP 150 to 220 mmHgNo indication/contraindication to treatmentIn-hospital vital signs, NIHSS, GCS and BP over 7 daysIntensive BP loweringSBP <140 mmHgStandard BP managementGuidelines SBP <180 mmHg)R34Independent 90 day outcome withmodified Rankin scale (mRS)N=2800 gives 90% power for7% absolute (14% relative)decrease (50% standard vs 43%intensive) in outcome
Patient Flow – 2839 patients recruitedOctober 2008 to August 20121382 (98.5%) for primaryoutcome1412 (98.3%) for primaryoutcome2839 Randomised28,829 Total estimated screened3 no consent1 missing baseline data2 lost to follow-up3 withdrew consent12 alive without mRS dataReasons for exclusion (n=3572)39% Outside time window16% Judged unlikely to benefit11% BP outside criteria8% Planned early surgery5% Refused21% Other reasons6411 Screening logs completed1403 Intensive BP lowering 1436 Standard BP lowering5 no consent1 missing baseline data5 lost to follow-up4 withdrew consent9 alive without mRS data
Systolic BP time trends1 hour - Δ14 mmHg (P<0.0001)6 hour - Δ14 mmHg (P<0.0001)Systolic BP controlMedian (iqr) time to treatment, hr - intensive 4 (3-5), standard 5 (3-7)Intensive group to target (<140mmHg)462 (33%) at 1 hour731 (53%) at 6 hoursMeanSystolicBloodPressure(mmHg)0110120130140150160170180190200R 15 30 45 60 6 12 18 24 2 3 4 5 6 7StandardIntensive////Minutes Hours Days / Time164153150139am pm am pm am pm am pm am pm am pmP<0.0001beyond 15minsTarget level36
safe - no increase in death or harmseffective – borderline significant effect on the primaryendpoint• secondary analyses - improved recovery of physical functioning andhealth-related quality of life in survivorsEarly intensive BP lowering treatment is37
Treatment effect smaller (4%) than expected 7% absolute,but:• active-comparison study on background therapies, some with BPlowering properties (i.e. mannitol)• equates to NNT 25 (greater than aspirin and near late use of rtPA inischaemic stroke)No clear time-dependent relationship of treatment• potential mechanisms beyond haematoma growth• benefits of BP control may take several hours to manifest• effects on haematoma growth and other results outlined in Symposiumthis afternoonINTERACT2 - issues38
INTERACT2 resolves longstanding uncertainty over the management ofelevated BP in acute ICHProvides evidence regarding safety and efficacy in a broad range of patientswith ICHDefines for the first time a medical therapy for the management of acuteICHAs BP lowering treatment is low cost, simple to implement, and widelyapplicable, the treatment should become standard of care to patients withICH in hospitals all over the worldConclusions39
Recommendation AHA 2010Hypertension is common during earlystates of ICH -> Expansion, Peri-hematoma edema and re-bleedingA systolic BP above 140 to 150 mmHg within 12 hours of ICH isassociated with more than double therisk of subsequent death ordependency.Association of low BP anddeterioration is not consistent likeischemic stroke.In patientspresenting with asystolic BP of 150to 220 mm Hg,acute lowering ofsystolic BP to 140mm Hg is probablysafe• Class IIa; Level ofEvidence: B
When to initiate oral antihypertensivemedication?After first 24-48 hours
Subarachnoid HemorrhageAsia Pacific Cohort Studies Collaboration demonstrated that hypertension wasan independent risk of SAH increased sharply with increase in systolic BPSAH incr ICP & decr cerebral perfusion causing global ischemiaInduces intense vasospasm in neighbouring vessels (4- 12 days) afterinitial bleed.Goal-dec 20-25% of MAP over 6-12 hrs but not <160/100.If vasospasm occurs later-inc BP with 3H(not proven)Preffred - lobetAvoid- nitrodilators
Hypertensive EncephalopathyWhen high perfusion pressure overwhelms cerebralautoregulation.Can lead to blindness, seizures, coma, gradually worseningheadache.Pathologically-cerebral edema, petechial hemorrhg,microinfarcts.Immediate Neuroimagng - to rule out ischemicstroke/hemorrhageHallmark is improvement in 12-24 hrs of BP redn.
HTN ENCEPH… DIFFN POINTSFocal neurological deficit is unusual withoutcerebral bleedPapilledema is almost always assoc with HtnencephMental staus improves by 24-48hrs-delayed in CNSbleedBrain dysfunction develops by 12-24 hrs in Htn butmore acutely with ischemic stroke/bleed.
HTN ENCEPH…Treatmentshort acting parenteral agents used.MAP should decrease by 15-20% over 2-3 hrs. .
Prevention of Stroke - TrialsDiuretics CCBs ACE-I ARBsALLHAT(JAMA2002)ALLHAT(JAMA 2002)HOPE ( ACCESS (Stroke 2003)ASCOT (Lancet2005)PROGRESS(Lancet 2002)MOSES (Stroke 2006)Long term control of Hypertension following strokereduces recurrence of stroke
BP Control as Primary Prevention of StrokeBoth lifestyle modification and pharmacological therapy, arerecommended (Class I; Level of Evidence A)Systolic BP should be treated to a goal of <140 mm Hg anddiastolic BP to <90 mm Hg because these levels are associatedwith a lower risk of stroke and cardiovascular events (Class I;Level of Evidence A).In patients with hypertension with diabetes or renal disease, theBP goal is <130/ 80 mm Hg (also see section on diabetes) (ClassI; Level of Evidence A).
Cerebral Small Vessel Disease (SVCD)n Incidence: 20-25% of Small vessel Infarcts (SVI) lacunar infarctsn Short term better prognosis but not long term
Cerebral Microbleeds (CMBs)n MRI – 4.7% - 24.4% in communityn Ischemic stroke 19.4%n Hemorrhagic stroke: 68.5%n Lobar distribution in Amyloid Angiopathyn Basal and Infratentorial in Hypertensive Vasculopathyn Hypertension, Diabetes and Low serum Cholesterol as predispositionA gradient-recalled echoandB susceptibility weightedimaging maps.Susceptibility-weightedimaging is more sensitivethan gradient-recalledecho to venous structures.