M. Mohsen Ibrahim, MD
Prof. of Cardiology-Cairo University
Address: 1 El-Sherifein St., Abdeen, -Cairo
Tel: (202) 794-8877 / 392-1777
Fax: (202) 794-8879
The Egyptian Hypertension Society - President Message - M.Mohsen Ibrahim, MD
New Oral Anticoagulant and Antiplatelet Drugs
President Massage Part1
Mohsen Ibrahim, MD
President of the Egyptian Hypertension Society
These are two massages which are a summary of a lecture I gave in Ismailia at the annual meeting of Suez Canal cardiology department and in Port-Said at summer meeting of the EHS. The first massage addresses anticoagulant drugs and the second is about antiplatelet therapy.
The subject is important for a number of reasons.
Majority of vascular events (coronary, cerebral and peripheral) are secondary to thrombotic or embolic occlusion of a major or an important artery. Antithrombotic therapy plays an important role in prevention and treatment of vascular events. In recent years, there were advances in drug therapy with the introduction of new oral anticoagulant and antiplatelet drugs. This review will discuss the mechanism of blood coagulation, role of blood platelets and the role of anti-thrombotic therapy.
Drugs used to treat thrombo-embolic disorders belong to one of three major classes:
Suppress the coagulation cascade. Include heparin, vitamin K antagonists (warfarin) and the new oral anticoagulants (NOACs) namely Apixaban, Rivaroxaban, Edoxaban, and Dabigatran.
Inhibit platelet activation, and aggregation. Include aspirin and adenosine diphosphate receptor blockers, such as Clopidogrel, Prasugrel and Ticagrelor.
Promote lysis of fibrin strands causing dissolution of thrombi, include tissue plasminogen activators ( tPA) such as Alteplase and Tenecteplase
It involves a series of enzymatic reactions that end in the formation of fibrin clots that seals the injured blood vessel and prevents blood loss.
Two pathways. Extrinsic and intrinsic are involved in the coagulation cascade that end on the activation of factor X which converts prothrombin into active thrombin. Thrombin changes soluble fibrinogen in plasma into insoluble fibrin. (see figure)
- Extrinsic pathway is activated when vascular endothelium is injured or disrupted e.g., following rupture of atherosclerotic plaque resulting in the exposure of subendothelial tissue and cells to the blood. Tissue factor (TF) which is a transmembrane glycoprotein expressed on subendothelial structures will initiate the extrinsic pathway by activating factor VII which is a plasma protein proenzyme (zymogen). TF and active factor VII convert prothrombin (factor II) into active thrombin (IIa).
- Intrinsic pathway involves a series of enzymatic reactions which activate inactive plasma enzymes (zymogens) into active enzymes. Intrinsic pathway is initiated by contact of coagulation factors in plasma with foreign materials e.g., prosthetic valve or collagen tissue in the blood. Inactive factor XII is activated to the active factor XII which activate factors XI, IX and VIII serially.
Active factor VIII converts factors X into active factor Xa.
Both extrinsic and intrinsic pathways convert upon factor X which when activated changes prothrombin (factor II) to thrombin (factor IIa).
Thrombin changes the plasma protein soluble fibrinogen to insoluble fibrin strands which are stabilized by factor XIII and form blood clot.
- Heparin is a mucopolysaccharide which interacts with antithrombin, an endogenous thrombin inhibitor made in liver to inactivate thrombin. Antithrombin (AT) is a globulin occurring naturally in the body. Heparin-AT complex binds to activated factors Xa, XIIa, XIa, and IXa and protein C.
- Heparin also mediates tissue factor pathway inhibitor mobilization.
Heparin can be administered both intravenously and subcutaneous. After subcutaneous injection, the anticoagulant effect is delayed for 1-2 hours. Both intensity and duration of anticoagulant effect increase with increasing doses.
Heparin is cleared through renal elimination and through binding on receptors on endothelial cells and macrophages.
Vitamin K antagonists: Warfarin
An oral anticoagulant which inhibits vitamin K reductase leading to depletion of vit K, which is essential for the activation of clotting factors II (thrombin), VII, IX and X.
Laboratory monitoring is necessary with warfarin therapy. Prothrombin time (PT) increases with depression of factors II, VII, and X. Normal PT is 12 seconds, and it should be kept twice normal value. Anticoagulant effect appears after about 3-5 days. Therapeutic INR values are usually achieved by day five of treatment. Initial dose is 10 mg/day for 2 days and maintenances dose is 1-10 mg/day according to INR.
New Oral Anticoagulants (NOACs)
- Apixaban - Rivaroxaban - Dabigatran - Edoxaban
- They overcome the limitations of warfarin which are the narrow therapeutic range, slow onset of action, slow offset of action, multiple drug, and dietary interactions, and require monitoring to maintain in therapeutic range. It is difficult to manage for invasive procedures.
- The new agents are given orally, have short half-lives, no INR monitoring is needed, cleared through the kidneys with few drug and food interactions.
- Dabigatran is a direct thrombin inhibitor given twice daily, while rivaroxaban, apixaban and edoxaban are direct factor Xa inhibitors.
- Doses of NOACs:
- Apixaban: 5mg BID reduced to 2.5mg BID in the elderly (>65 years), chronic kidney disease (CKD), and small body weight (<40 Kg).
- Rivaroxaban: 20 mg once daily reduced to 15 mg/ day in CKD.
- Dabigatran:150 mg BID reduced to 75 mg BID in CKD.
- Edoxaban: 60 mg once/day.
Limitation of NOACs:
- Short half-life -Expensive - Renal function determines the dose - Not suitable for valvular AF - There is no known antidote.
Best candidates for NOACs:
Patients with unstable INR on warfarin with good renal and hepatic functions, patients younger than 75 y/o, no mechanical valves and no history of lower GI bleeding.
President Massage (June 2021)
The Making of New Guidelines
Mohsen Ibrahim, MD
President of the Egyptian Hypertension Society
Within the coming weeks the new EHS dyslipidemia guidelines will be available for the medical community. In the following president message I will outline the steps in the preparation of guidelines and the questions addressed when making new guidelines.
- How important is the subject of guidelines?
Coronary heart disease (CHD) is common among Egyptians and possibly its prevalence is on the rise in recent years based upon authors personal practice. Atherosclerotic risk factors namely cigarettes smoking, obesity, hypertension, unhealthy life style and poor dietary habits are common furthermore the number of patients with diabetes mellitus has almost doubled in the last decades. Dyslipidemia is poorly managed by Egyptian doctors. According to the Egyptian DYSIS study (2013) , despite chronic statin treatment , two third of Egyptian patients had elevated LDL-C levels .
In Egypt mortality secondly to CHD is rapidly rising, According to WHO statistics the age standardized mortality rates from CHD are one of the highest worldwide.
Statin thereby is one of the greatest therapeutic advances in modern medicine, since they lower the risk of heart attack, stroke and death in high risk patients. The initiation and monitoring of statin therapy is an important chapter in Egyptian guidelines.
- Why Egyptian guidelines? Why not follow the international guidelines?
The majority of international guidelines were developed in Western or rich countries with different ethnic background, dietary habits, life style and health care system. Majority of Egyptians are not medically insured and pay out of their own pockets for drugs and medical services. Therefore the new Egyptian Guidelines have to make a compromise between what is ideal supported by clinical trials and what is feasible. Unfortunately there are limited data and few clinical trials addressing the question of dyslipidemia among Egyptians. Therefore many of the recommendations in Egyptian guidelines are based upon consensus and expert opinion, Furthermore the international guidelines are lengthy Some exceeding 300 pages, somewhat complicated, not familiar to Egyptian doctors and may be difficult to apply.
- How the new Egyptian guidelines will differ from other guidelines?
An important component in management of dyslipidemia is CV risk assessment and identifying high risk individuals who might need immediate and aggressive therapy. The international guidelines use risk scoring systems which are not familiar to the majority of Egyptian doctors and their validity was not tested in Egyptian patients.
The risk scoring in the Egyptian guidelines was based upon the number and intensity of CV risk factors. Patients were categorized into four groups:
- Low risk with no or just a mild risk factor
- Moderate risk with 2 -3 risk factors not including diabetes
- High risk patients with more than 3 CV risk factors, very high single risk factor, long standing diabetes or CKD.
- Very high risk patients with established atherosclerotic CV disease – coronary, cerebral, peripheral, carotid and aortic. Patients with acute coronary syndromes or acute stroke belong to this very high risk group.
The target LDL-C was a bit higher in the Egyptian guidelines. Though it is an established fact that the lower LDL-C the better and very low level (< 50mg / dl )are recommended in the very high risk patients ,this may not be feasible unless high dose of statins are prescribed or very expensive medications (PCSK9- inhibitors ) are administrated . This policy though it may look ideal, it cannot be followed in developing countries with low resources settings and for prolonged lifelong treatment.
- Who are the target audience?
Cardiologist and physicians in different specialties particularly endocrinology, diabetes and metabolism will find these guidelines useful in every day clinical practice.
- How guidelines were made?
a) The guidelines main author reviewed eleven national and international guidelines in addition to recent world literature. Important information was marked and collected as a reference.
b) A guidelines writing group was selected by the main author
c) Guidelines were classified into 7 chapters after an introduction , these chapters covered :
- Lipoprotein metabolism
- Assessment of global CV risk
- When to initiate and how to monitor statin therapy
- What is the role of other lipid lowering drugs
- Management of dyslipidemia in specific groups
- When and how to treat hypertriglyceridemia?
- Non pharmacological treatment.
d) Each of the writing group members was assigned one or more chapters.
e) Writing group members met on three occasions and a provisional draft was prepared and approved by all members
f) An advisory board was selected from experts in different specialties including general medicine, cardiology, endocrinology, and nephrology.
g) The final draft prepared by the writing group was send to the advisory board members for revision, comments and approval.
h) The writing group and advisory board met in joint meetings for final approval of guidelines and discussing future plans for guidelines dissemination and implementation.
- Guidelines dissemination and implementation
- After being approved by the advisory board guidelines are printed and sent to the heads of cardiac and medical departments in different universities, deans of medical schools and ministry health authorities.
- An educational program based upon the guidelines is prepared for physicians education to be organized in national meetings
- Guidelines will appear on the website of the EHS.
New Oral Anticoagulant and Antiplatelet Drugs
M. Mohsen Ibrahim, MD
ROLE OF BLOOD PLATLETS
Form a platelet plug or thrombus to prevent blood loss when a blood vessel is injured. They are the first hemostatic mechanism.
Platelets normally circulate in blood as inactive tiny discs (2-3 microns in diameter) without nuclei and have smooth cell membrane which is very rich in platelet receptors.
When endothelium is injured or disrupted with exposure of the sub-endothelial matrix proteins and cells, adhesion proteins mainly collagen and von Willebrand factor adhere to platelets leading to platelets activation.
Platelet activation results in: (1) change in platelet shape from smooth discs to spiny spheres, (2) secretion of platelet contents such as serotonin, ADP, arachidonic acid, thrombin, fibrinogen, and adhesion proteins, (3) exposure and activation of GP IIb/IIIa receptors which are fibrinogen receptors. Fibrinogen forms cross bridges between activated platelets resulting in formation of platelet aggregates.
In the absence of cardiac arrhythmias and valvular heart disease, prevention of coronary thrombosis mainly relies on antiplatelet therapy.
Inhibits cyclooxygenase enzyme (coxi), an enzyme responsible for the generation of thromboxane. Coxi converts arachidonic acid into the prostaglandin GZ, a precursor of prostaglandin PGH2.
PGH2 is either converted into prostacyclin-by-prostacyclin synthase present in endothelial cells or converted into TXA2 by thromboxane synthase in platelets.
Low dose aspirin inhibits platelet synthesis of thromboxane, while maintain endothelial synthesis of prostacyclin.
In addition to antiplatelet activity aspirin reduces markers of inflammation.
- P2Y12 Inhibitors: Thienopyridines:
Clopidogrel – Prasugrel – Ticagrelor
Block the binding of adenosine diphosphate (ADP) to a specific platelet receptor P2Y12.
Thienopyridines indirectly inhibit the activity of other platelet agonists such as arachidonic acid, collagen, thrombin, epinephrine, and serotonin. Also, they inhibit platelet aggregation induced by collagen and thrombin.
Clopidogrel and prasugrel are prodrugs, while ticagrelor is an active drug with additional active metabolites. Antiplatelet potency is greatest with prasugrel and less with clopidogrel and moderate with ticagrelor.
- Clopidogrel Vs. Ticagrelor
Ticagrelor is more effective, and for patients with ACS, it quickly inhibits platelet aggregation, while clopidogrel is less effective.
Clopidogrel is a prodrug, its activation can be influenced by genetic factors with some patients have clopidogrel resistance. Its onset of action is somewhat delayed and initial large loading dose is required.
In ACS treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death, myocardial infarction, and stroke without an increase in major bleeding.
Dual Antiplatelet Therapy (DAPT)
Combination of aspirin with oral antiplatelets (Clopidogrel, Ticagrelor).
Goals of DAPT are to prevent new ischemic events and prevent stent thrombosis.
1. Post-ACS event: patients have more thrombotic phenotype, 12 months DAPT is recommended regardless of stent placement.
2. Stable ischemic heart disease is less thrombotic phenotype and DAPT is considered if a stent is placed.
3. Severe diffuse atherosclerosis, high risk patients with peripheral artery disease and cardiovascular disease specially if combined with CAD.
Clopidogrel with aspirin are given to patients with TIA or minor stroke. Treated within 24 hours after onset of symptoms. The combination is superior to aspirin alone for reducing the risk of stroke in the first 90 days.
Duration of DAPT:
- Following ACS with stent or not: 12 months.
- Stent placed in non-ACS setting: 6 months.
The ESC/EASD guidelines highlighted the superiority of modern P2Y12 inhibitors and encouraged the use of these agents for DAPT in diabetes.
Long term therapy with aspirin and ticagrelor in diabetes patients with established CAD- for a median of 33 months-reduced major adverse cardiac events beyond 12 months of the coronary event.
More studies are required to understand the best strategy for long-term antithrombotic therapy in diabetes. The enhanced thrombotic environment in diabetes calls for alternative antithrombotic treatment strategies in primary and secondary vascular protection.
Aspirin + P2Y12 inhibitor + Oral anticoagulant
Rarely indicated beyond are month duration.
P2Y12 inhibitor (clopidogrel, ticagrelor) are preferred over aspirin: NOACs are preferred over warfarin.
Continue triple therapy for maximum one month post-hospital discharge.
When transition to dual therapy drop aspirin and continue P2Y12 inhibitor.
Choose NOAC rather than warfarin unless contraindicated or cost.
When Prescribing New Antiplatelet drugs consider the following factors:
1. Potency: Prasugrel most potent, followed by ticagrelor, then clopidogrel
In the ACS setting, we tend to prefer more potent agents like ticagrelor or prasugrel in the absence of contraindications
2. Bleeding risk: Increased bleeding risk is always the tradeoff of increased potency. We avoid prasugrel in patients age > 75, history of TIA/stroke, and hepatic dysfunction Also avoid ticagrelor in patients with history of ICH
3. Feasibility- Side effects: Ticagrelor inhibits adenosine reuptake, which can cause bradycardia and dyspnea, sometimes resulting in patient self-discontinuation.
4. Dosing frequency: Clopidogrel and prasugrel are once per day, while ticagrelor is twice per day
5. Price: Clopidogrel is the least expensive.
Hypertension – Drug treatment Strategies in Daily practice
M. Mohsen Ibrahim, MD
This massage is derived from a lecture I gave in an international meeting held in Cairo this year. The information in the lecture was derived from world literature, recent guidelines and author’s personal experience while caring for hypertensive patients over more than fifty years.
The massage addresses the following six questions:
- When to initiate drug treatment for hypertension?
- Which drug is the first choice?
- How to monitor drug treatment?
- What to do about BP variability?
- How to manage poor BP control and resistant hypertension?
6. What is the role of new anti-hypertensive drugs?
The massage consist of 2 parts in part I will address the first two questions.
1. When to initiate drug treatment for hypertension?
This is possibly the most important question. The decision to initiate drug treatment should not be taken lightly because once drug treatment for hypertension is started, it will continue indefinitely, since there is no cure from established essential hypertension. Before initiating treatment the physician should confirm the diagnosis of hypertension and assess the need and urgency for drug treatment. Accurate and repeated BP measurements are required before making the diagnosis in the office. Unless there is an urgency more than one office visit is required. Home BP measurements are sometimes necessary before making the diagnosis. However, 24 hours ambulatory BP measurements (ABPM) are possibly the best diagnostic method. We can reduce the number of patients starting treatment by 25 % if we use ABPM.
At initial evaluation it is necessary to assess the patient’s global CV risk and presence of target organ damage in order to determine the need and urgency for drug treatment.
The following table shows the definition and classification of hypertension based upon office readings according to recent guidelines
- Normal BP: <130/85 mmHg
- High normal BP: 130-139 and /or 85-89 mmHg
- Grade I HTN (mild): 140-159 and/or 90-99 mmHg
- Grade II HTN ( moderate): ≥160-179 and/or 100-109 mmHg
- Grade III HTN ( severe): ≥180 and / or ≥ 110 mmHg
- Isolated systolic HTN: ≥140 and ≤90 mmHg
The criteria for diagnosis of HTN very according to the method of measurement of BP. For the clinic (office) BP > 140/90 mmHg, for 24 hours ABPM > 130/80 mmHg, for home BP measurements > 135/85 mmHg and for automated office measurements > 135/85 mmHg. Home BP measurements are more reliable predictor of prognosis than clinic BP.
What is next after establishing the diagnosis of HTN?
Unless there is an urgency a trial of non-pharmacologic treatment in terms of lifestyle modification ( LSM) should be started and continued in parallel with drug therapy. Non- pharmacologic treatment includes weight reduction if obese, a healthy diet (DASH diet) rich in fruits, vegetables, fish, whole grain and cereals. Limiting salt intake to less than 5 gram sodium chloride / day is recommended, while avoiding sugary and high caloric drinks and foods rich in animal fat. Regular physical exercise e.g 30 minutes brisk walking/day while avoiding tobacco and alcohol are stressed.
Guidelines differ regarding the duration of the period of initial BP monitoring before initiating drug treatment. French recommended commencing pharmacologic treatment at stage 1- HTN regardless of other CV risk factors. However, the majority of guidelines recommended a trial period of LSM before drug therapy. The period varies from 3 months in the AHA/ACC guidelines and 6-12 months in ASH/ISH guidelines.
Immediate, initiation of drug therapy on first office or hospital visit according to Egyptian guidelines is indicated in hypertensive emergencies, when BP exceeds 210/120 mmHg on 3 consecutive measurements 2-3 minutes apart after excluding a panic attack or when BP is greater than 180/110 mmHg on 3 consecutive measurements in presence of target organ damage , symptomatic CV disease or chronic kidney disease(CKD).
2. Which drug is the first choice?
Anti-hypertensive drugs belong to five different pharmacologic groups besides new emerging drugs. The pharmacologic groups are thiazides and thiazide derivatives, RAS blockers, ARBs, sympatholytics and vasodilators.
These drugs address four different presser mechanisms responsible for BP elevation namely sympathetic over activity, RAS activation, increased blood volume and increased arterial stiffness. The choice of anthi-hypertensive drug group will depend upon patient’s age, CV risk factors, clinical CV disease and comorbidities such as diabetes mellitus (DM), CKD, obesity, heart failure, coronary artery disease (CAD), prostatitic hypertrophy, pregnancy, COPD, anxiety, migrain and tachycardia.
Diuretics are recommended in elderly patients, presence of heart failure (HF), CKD, renal failure and isolated systolic HTN.
Diuretics are the only drug class that targets a known cause of HTN, namely increased blood volume. Chlortholidone is superior to hydrochlorathiazide (HCTZ) in preventing CV events. Thiazides, or thiazide-like diuretics are effective down to an eGFR of 25-30 ml/min/ 1.73 m2. Below this eGFR level a long acting loop diuretic e.g (torsemide) should be used.
The side effects of diuretics include excess urination, hypokalemia, hyperuricemia and impaired glucose tolerance.
Calcium channel blockers (CCB) e. g. amlodipine are recommended in elderly patients and presence of CAD or peripheral arterial disease, pregnancy, excess BP variability and arrhythmias ( non-dihydropyridine CCBs). The side effects of CCBs include ankle swelling, headache and flushing. Recent CCBs like nicardipine have the advantage of less ankle edema and greater renal protection.
Beta-drenergic blockers (BABs) are indicated in presence of CAD, HF, arrhythmias, tremors, migrain, tachycardia, anxiety, hyperkinetic circulation and young age. Side effects of BABs are bradycardia, fatigue, impotence, exacerbation of bronchial asthma, cold extremities and worsening symptoms of peripheral vascular disease.
ACE inhibitors and ARBs are the drugs of choice in diabetic patients, HF and CKD. Side effects of ACE inhibition are cough, allergic reactions, hyperkalemia and rise in serum creatinine. ARBs have the advantages of less side effects (cough) compaired to ACE inhibitors. ARBs because of rare side effects enjoy the longest adherence to treatment.
RASBs Independent of their antihypertensive effect, have a cardioprotective effect in patients with high risk of CV disease.
ARBs adherence to treatment after 12 months is in 64% of patients compaired to 58% with ACE inhibitors, 50% with CCBs, 43% with BABs while thiazide diuretics have the lowest rate of 38% according to data from USA.
Less than half of all hypertensive patients will attain target BP with monotherapy, while 75% do not have optimal BP control. On the other hand 30% of patients will need 3 or more drugs in combination to attain target BP levels. The ability of any agent to achieve target BP (< 140/90 mmHg) when used alone does not exceed 20-30%.
When selecting first line therapy there are a number of compelling indications and choice of drug therapy will be individualized. The drugs of choice in hypertensive patients with angina are BABs ± CCBs, after MI or CABG are BABs ± (ACEIs or ARBs in HF diuretics + BABs+ RASBs. In cerebrovascular disease or PAD, RASBs+ CCBs, in pregnancy methyl dope ( aldomet) and CCBs, in prostatic hypertrophy alpha adrenergic blockers (doxazosin). BABs are recommended in presence of migrain, tremors and situational anxiety.
Hypertension – Drug treatment Strategies in Daily practice
3. How to monitor drug treatment?
Clinical evaluation and BP check are required every 2-4 month, while laboratory
monitoring for blood chemistry and ECG may be needed once / year unless there are
Fig 4: Initiation and Monitoring of Drug Therapy
Hypertension – drug treatment strategies in daily practice. M. Mohsen Ibrahim
Antihypertensive drugs may require a period of up to two months to achieve maximal hypotensive effect. On the other hand a significant reduction in BP can be achieved after two weeks of therapy with many drugs, particularly combination therapy. It is not
recommended to change drugs at short intervals. It is advisable to recheck BP at one to two monthly interval until it remains at target level for two consecutive visits, then recheck at 3-6 months depending upon the CV risk profile. Frequency of checking BP
(interval to next visit) in low to intermediate risk patients is at 1-2 months intervals, while in high risk patients at two weeks intervals. Recent guidelines define BP control as < 130/80 mmHg in the office and <125/75 mmHg as determined by 24 hours ABPM
Fig 5: Monitoring of drug therapy frequency of checking BP
To improve patients compliance with antihypertensive drugs, patients education is recommended stressing the fact that HTN is silent, dangerous if not treated , requires life-long treatment and monitoring. Physician should prescribe affordable drugs while
drug administration is preferably once daily with minimal number of tablets, better a single pill combination.
4. What to do about BP variability?
Levels of BP are liable to fluctuation and can change from minute to minute and from day to day . These fluctuations in BP can generate anxiety and confusion regarding diagnosis and treatment.
Short term BP variability may be instantaneous within seconds as occurs during sleep, pain, posture , emotions, talking, distended urinary bladder or within minutes after smoking, meals, hypoglycemia or within hours following medication or circadian-diurnal changes. Long term or office visit to visit variability can be spontaneous , due to drugs or rarely pheochromocytoma.
Guidelines regard variability of BP as noise that has to be removed from the diagnostic process and that HTN should not be diagnosed on the basis of episodic rises in BP unless mean BP is raised ( ESH 2007 guidelines). Guidelines differ regarding the management of BP variability. Some stress the need to do 24 hours ABPM or home measurements (ESH 2007), others stress the need to confirm BP elevation in 2-5 subsequent visits ( JNC, BHS and Canadian guidelines).
The treatment implication of reducing visit to visit BP variability are uncertain and there is no direct evidence that a reduction of visit to visit variability (VVV) is beneficial. However, CCBs and diuretics tend to decrease VVV, whereas BABs and RASB seem to do the opposite.
5. How to manage poor BP control and resistant hypertension?
Failure to achieve optimal BP control is responsible for 60% of cerebrovascular accidents, 50% of coronary events, for 7.1 million death/year and 64.3 million serious disabilities/ year. It is predicted that over the next 10 years health costs of non-optimal BP are likely to reach over 908 billion dollar if BP remains at current levels. Optimal BP control varied in hypertension surveys from 23% in USA, 24% in France, 16% in Canada, 8% in Egypt and 5% in China.
The causes of poor BP control may be drug, lifestyle or physician related. Drug related causes include limited access to treatment, poor adherence or inadequate,dosage. Lifestyle causes are unhealthy diet, excess salt intake, obesity, sedentary
lifestyle and continuous emotional stress. Lack of adherence to treatment guidelines, inadequate follow-up, therapeutic inertia and lack of adequate time with the patient are physician and health system related causes.
In an Egyptian survey of 1534 hypertensive patients up to 79% of patients quite treatments within the first year. Only 10-15% of originally treated patients were still adherent to treatment after five or more years.
Definition (AHA 2018) of resistant HTN:
Above goal BP despite 3 or more BP medications commonly including a long acting
CCB, RAS blocker and a diuretic at maximally tolerated doses and appropriate
dosing frequency, excluding white coat HTN with ABPM or home monitoring and
medication non-adherence. This definition excludes causes of false resistance.
Management of resistant HTN
First exclude pseudo-rsistance by accurate BP measurement, ensuring adherence to lifestyle modification and antihypertensive therapy. ABPM (24 hours) and if unavailable use home BP in order to exclude white-coat HTN. Also history of intake of pressor drugs and obstructive sleep apnea should be excluded, then increase the dose of diuretics since blood volume expnasion is an important cause of resistant HTN. Long acting loop diuretic is added and if fail add spironolactone.
Assess for secondary HTN if still BP is not controlled after the previous measures. Causes include primary aldosteronisne , renal parenchymal disease, renal artery stenosis, pheochromocytomar, paraganglioma, Cushing syndrome, coarctation of
the aorta and other endocrcine causes.
What to do if there is inadequate BP response?
1. Exclude :
a. Pseudo resistance and white coat effect
b. Intake of pressor drugs
c. Obstructive sleep apnea
2. Stress lifestyle modification:
a. Limiting salt intake
b. Treat obesity
c. Stress management
3. Pharmacologic treatment:
a. Blood volume control: aggressive diuresis-use loop diuretics
b. Aldactone/ spironolactone
c. BABs if heart rate is >70 b/m
d. α-blockers and vasodilators if heart rate < 70 b/m
4. If fail screen for secondary hypertension
6. What is the role of new anti-hypertensive drugs?
Many of the following drugs are not yet established standard treatment for HTN, but
may be part of the future drug therapy of HTN. The list of new antihypertensive drugs
1. New calcium channel blockers
2. Endothelin antagonists
3. Combined ARB with a Neprilysin inhibitor
4. Aldosterone synthase inhibitors
5. Natriuretic peptide receptor agonists
6. Imidazole’s: centrally acting drugs with less side effects
7. Neutral endopeptidase inhibitors : inhibit metabolism of atrial natriuretic peptide .
8. Mineralocorticoid receptor antagonists.
1. New calcium: channel blockers:
Third generation CCB have less incidence of peripheral edema in hypertensive patients which improves drug persistence in treated patiens. Examples of new CCBs are lercanidipine, lacidipine and manidipine
2. Endothelin antagonists:
Because of their side effects ( headaches and fluid retention) they are only used in resistant hypertension or hypertension of renal disease.
3. Combined ARB with a Neprilysin inhibitor:
Neprilysin is the enzyme when breaks down natriuretic peptides. Sacubitril is a neprilysin inhibitor which enhances the vasodilation of these peptides. The combination with an ARB ( valsartan) is commercially available ( Entresto) which is used in treatment of heart failure and resistant hypertension.
4. Aldosterone synthase inhibitors:
LCI699 is the first orally active aldosterone synthase inhibitor for human use. It decreases plasma and urine aldosterone concentration. New compounds as potent and more selective than LC I 699 are currently being tested as treatment for mineralocorticoid dependent CV and renal disease.
5. Natriuretic peptide receptor agonists:
Increased natriuresis and diuresis, elevate plasma cyclic guanosine monophosphate and reduce systemic BP. PL- 3994 given subcutaneous with prolonged half life administered as an adjunct to standard therapy in patients with resistant HTN. It has reduced affinity for the natriuretic peptide clearance receptor and increased resistance to neprilysin.
6. Mineralocorticoid receptor antagonists:
Spironolactone has significant progesterone and antiandrogenic activity. Eplerenone is more selective MRA but is less potent. Finerenone, a non-steroidal MRA is more selective than spironolactone and more potent than eplerenone
Summary and Conclusion
Drug treatment of HTN has changed the outcome of hypertensive patients and is one of the most successful therapeutic achievements.
However, drug treatment does not provide cure for HTN, therefore it has to be continued indefinitely to maintain BP control. The first and possibly most critical question is when to start drug treatment. The answer depends upon the accurate diagnosis of HTN and the detection of other CV risk factors. The threshed for diagnosis of HTN depends upon the method of BP measurement and recommendation of guidelines. Office measurements have obvious limitations and recent guidelines do not depend upon office readings to establish the diagnosis and initiate therapy. ABPM and automated office measurements provide more accurate and reliable methods to diagnosis HTN. After deciding the need for drug treatment the next question is which drug to choose as initial therapy. This will depend upon patient’s age, drug cost, presence of target organ damage and co-morbid conditions. Drug combination therapy is recommended in the majority of patients mainly ACEIs, ARBs combined with CCBs and or thiazide diuretics. These agents are specially recommended in patients with CKD, DM, HF. In presence of CAD, BBs are the first choice. In elderly atients and in presence of isolated systolic HTN,CCBs and diuretics are drugs of first choice. BBs are recommended in presence of CAD, HF, tachycardia, anxiety, migraine and arrhythmias. Drug therapy requires careful monitoring. BP should be checked at 2-4 weekly intervals after initiation of treatment, then at 2-6 monthly intervals depending upon BP level and CV risk profile. BP variability is a
common problem and diagnosis of HTN should not be made unless the BP is persistently elevated. Failure to achieve optimal BP control is another common problem: Interruption and/or inadequate drug therapy is the main cause. Patients education is mandatory, stressing the silent nature of HTN and the need to continue drug therapy indefinitely. Doctors should be aware of the recent guidelines and the importance of single pill combination and regular BP monitoring. Management of true resistant HTN (after exclusion of white coat HTN), depends upon accurate diagnosis, lifestyle modification ( low salt) weight reduction, avoiding presser medications and treatment of obstructive sleep apnea. Increasing the dose of diuretics and use of spironolactone are recommended in truely resistant cases. Finally there is a rapidly growing list of new ntihypertensive drugs which are undergoing clinical trials and can be used as a last resort in truely resistant hypertensive patients.